Antithrombogenic hollow fiber membranes and filters

ABSTRACT

The invention relates to extracorporeal blood circuits, and components thereof (e.g., hollow fiber membranes, potted bundles, and blood tubing), including 0.005% to 10% (w/w) surface modifying macromolecule. The extracorporeal blood circuits have an antithrombogenic surface and can be used in hemofiltration, hemodialysis, hemodiafiltration, hemoconcentration, blood oxygenation, and related uses.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.12/780,200, filed May 14, 2010, which claims benefit from U.S.Provisional Application No. 61/178,861, filed May 15, 2009, herebyincorporated by reference.

BACKGROUND OF THE INVENTION

The invention relates to antithrombogenic extracorporeal blood circuitsand components thereof, such as hollow fiber membranes, blood tubing,and filters, and their use in hemofiltration, hemodialysis,hemodiafiltration, hemoconcentration, blood oxygenation, and relateduses.

For a treatment of a patient suffering from renal failure, various bloodpurifying methods have been proposed in which blood is taken out fromthe living body of the patient to be purified and the purified blood isthen returned into the body. For example, the blood purification methodsutilizing extracorporeal circulation are classified into the followingtypes: hemodialysis (HD) by diffusion, hemofiltration (HF) whichperforms body fluid removal/substitution by ultrafiltration, andhemodiafiltration (HDF) in which HD and HF are combined.

The above-mentioned methods are implemented using a hemodialyzer. Thedialyzer is the piece of equipment that actually filters the blood ofwaste solutes and fluids (e.g., urea, potassium, creatinine, and uricacid). Almost all dialyzers in use today are of the hollow-fibervariety. A cylindrical bundle of hollow fibers, whose walls are composedof semi-permeable membrane, is anchored at each end into pottingcompound (a sort of glue). This assembly is then put into a clearplastic cylindrical shell with four openings. One opening or blood portat each end of the cylinder communicates with each end of the bundle ofhollow fibers. This forms the “blood compartment” of the dialyzer. Twoother ports are cut into the side of the cylinder. These communicatewith the space around the hollow fibers, the “dialysate compartment.”Blood is pumped via the blood ports through this bundle of very thincapillary-like tubes, and the dialysate is pumped through the spacesurrounding the fibers. Pressure gradients are applied when necessary tomove fluid from the blood to the dialysate compartment.

Hemodialysis is an important procedure that plays the role of anartificial kidney and replaces all vital functions due to chronic oracute kidney failure. The dialyzer may be used for the treatment ofpatients with renal failure, fluid overload, or toxemic conditions, andcan be configured to perform HD, HF, HDF, or hemoconcentration.

While the blood is being transported to and from the body or cleaned inthe dialyzer, an anticoagulant, such as heparin, may be added to preventclotting or thrombosis. For patients receiving continuous renalreplacement therapy (CRRT) (i.e., continuous dialysis 24 hours/7 days aweek), heparin is typically given as a bolus systemically to preventclogging of filter membranes during dialysis due to coagulation ofblood. In cases where no heparin is administered filters clog 27% of thetime, while with heparin filters clog 17% of the time (see Richardson etal., Kidney International 70:963-968 (2006)). For patients receivingintermittent hemodialysis (IHD) (intermittent dialysis of about 4 hourstwice daily), typically no heparin is administered. During IHD thefilters clog 20-30% of time (see Manns et al., Critical Care Medicine31:449-455 (2003)). When the filters clog, the dialysis procedure isinterrupted, and the filters are flushed with saline solution to clearthe thrombus. In patients undergoing chronic hemodialysis (e.g.,hemodialysis for extended hours at a time and with multiple sessionsduring a week) it is common to use heparin in bolus amounts to reducethe rate of filter clogging.

While advantageous, the use of heparin in some patients can becomplicated by allergic reactions and bleeding, and can becontraindicated for use in patients taking certain medications.

Some medical procedures require the use of extracorporeal oxygenatingmethods, where blood is taken out from the living body of the patient tobe oxygenated and the oxygenated blood is then returned to the body. Forexample, oxygenator devices implementing such extracorporeal oxygenatingmethods include heart-lung bypass units or extracorporeal membraneoxygenation (ECMO) machines used during open heart surgery, such ascoronary artery bypass grafting (CABG) and cardiac valve replacement, orused to treat respiratory distress syndrome or respiratoryinsufficiencies. During open heart surgery, devices forhemoconcentration can also be used to increase various blood componentswithin the patient, thus minimizing the risk of post-operative bleeding.These hemoconcentrators can be used in-line with an extracorporealcircuit that includes an oxygenator device, such as a heart-lung bypassunit.

Based on these treatments that require the use of pumping blood out ofand into a patient, there is a need for extracorporeal blood circuitsthat have reduced thrombogenicity. In particular, there is a need formethods and compositions to provide a polymeric component of anextracorporeal blood circuit with a surface that minimizes the rate ofthrombosis upon exposure to blood.

SUMMARY OF THE INVENTION

The methods and compositions of the invention features extracorporealblood circuits, and components thereof (e.g., hollow fiber membranes,potted bundles, and blood tubing), including 0.005% to 10% (w/w) surfacemodifying macromolecule.

In a first aspect, the invention features an extracorporeal bloodcircuit including a polymeric component, where the polymeric componentincludes a base polymer admixed with from 0.005% to 10% (w/w) of asurface modifying macromolecule (e.g., from 0.005% to 0.1% (w/w), from0.005% to 5% (w/w), from 0.1% to 0.3% (w/w), from 0.1% to 5% (w/w), from0.1% to 10% (w/w), from 0.05% to 5% (w/w), 0.05% to 8% (w/w), from 1% to5% (w/w), from 1% to 8% (w/w), from 1% to 10% (w/w), and from 2% to 10%(w/w)), where the polymeric component has a surface positioned tocontact the blood when the extracorporeal blood circuit is in use, andwhere the surface is antithrombogenic when contacted with the blood. Inone embodiment, the thrombi deposition at the surface is reduced by atleast 10%, 20%, 40%, 60%, or 80% (e.g., from 10% to 95%, from 10% to80%, from 20% to 95%, from 35% to 85%, or from 40% to 80%) whencontacted with blood. In another embodiment, the extracorporeal bloodcircuit has an increased average functional working life of at least110%, 125%, 150%, 200%, or 400% (e.g., from 110% to 1,000%, from 200% to900%, or from 300% to 900%). In yet another embodiment, theextracorporeal blood circuit reduces adverse advents in a subjectreceiving blood passing through the extracorporeal blood circuit.

Any of the extracorporeal blood circuits described herein can includeone or more of: a hollow fiber membrane of the invention; a pottedbundle of the invention; or a blood tubing of the invention.

In a second aspect, the invention features a hollow fiber membrane, thehollow fiber membrane including a base polymer admixed with from 0.005%to 10% (w/w) surface modifying macromolecule (e.g., from 0.005% to 0.1%(w/w), from 0.005% to 5% (w/w), from 0.1% to 0.3% (w/w), from 0.1% to 5%(w/w), from 0.1% to 10% (w/w), from 0.05% to 5% (w/w), 0.05% to 8%(w/w), from 1% to 5% (w/w), from 1% to 8% (w/w), from 1% to 10% (w/w),and from 2% to 10% (w/w)), where the hollow fiber membrane isantithrombogenic when contacted with blood. In one embodiment, thethrombi deposition on the hollow fiber membrane is reduced by at least10%, 20%, 40%, 60%, or 80% (e.g., from 10% to 95%, from 10% to 80%, from20% to 95%, from 35% to 85%, or from 40% to 80%) when contacted withblood. In another embodiment, the hollow fiber membrane has an operatingpressure after 4 hours of use that is reduced by at least 10%, 20%, 30%,40%, or 50% (e.g., from 10% to 95%, from 10% to 80%, from 20% to 75%,from 25% to 45%, or from 30% to 80%). In yet another embodiment, thehollow fiber membrane reduces adverse advents in a subject receivingblood passing through the hollow fiber membrane. In certain embodiments,the base polymer is selected from the group consisting of a polysulfone(e.g., poly(oxy-1,4-phenylenesulfonyl-1,4-phenyleneoxy-1,4-phenyleneisopropylidene-1,4-phenylene) orpolyether sulfone), a polyacrylonitrile, a cellulose acetate, acellulose di-or tri-acetate, a polyimide, a poly(methyl methacrylate), apolycarbonate, a polyamide, a polypropylene, and a polyethylene. Infurther embodiments, the hollow fiber membrane further includes ahydrophilic pore forming agent (e.g., polyvinylpyrrolidone, ethyleneglycol, alcohols, polypropylene glycol, and polyethylene glycol, ormixtures thereof). In one embodiment, the hollow fiber membrane includesfrom 80% to 96.5% (w/w) (e.g., from 80% to 95%, from 80% to 90% (w/w),from 85% to 90% (w/w), and from 90% to 95% (w/w)) of the base polymer,from 3% to 20% (w/w) (e.g., from 3% to 15% (w/w), from 3% to 7% (w/w),from 3% to 5% (w/w), and from 5% to 10% (w/w)) of the hydrophilic poreforming agent, and 0.005% to 10% (w/w) (e.g., from 0.005% to 0.1% (w/w),from 0.005% to 5% (w/w), from 0.1% to 0.3% (w/w), from 0.1% to 5% (w/w),from 0.1% to 10% (w/w), from 0.05% to 5% (w/w), 0.05% to 8% (w/w), from1% to 5% (w/w), from 1% to 8% (w/w), from 1% to 10% (w/w), and from 2%to 10% (w/w)) of the surface modifying macromolecule.

In a third aspect, the invention features a potted bundle of hollowfiber membranes within an encasement including: (a) an array of hollowfiber membranes, the array of hollow fiber membranes having lumens, afirst set of fiber ends, and a second set of fiber ends; (b) the firstset of fiber ends being potted in a potting resin which defines a firstinternal wall near a first end of the encasement; and (c) the second setof fiber ends being potted in a potting resin which defines a secondinternal wall near a second end of the encasement, where the lumens ofthe hollow fiber membranes provide a path for the flow of blood from thefirst internal wall to the second internal wall, and where the pottingresin includes from 0.005% to 10% (w/w) surface modifying macromolecule(e.g., from 0.005% to 0.1% (w/w), from 0.005% to 5% (w/w), from 0.1% to0.3% (w/w), from 0.1% to 5% (w/w), from 0.1% to 10% (w/w), from 0.05% to5% (w/w), 0.05% to 8% (w/w), from 1% to 5% (w/w), from 1% to 8% (w/w),from 1% to 10% (w/w), and from 2% to 10% (w/w)). In certain embodiments,the bundle has a prolonged working life. In some embodiments, the bundlehas an increased average functional working life of at least 110%, 125%,150%, 200%, or 400% (e.g., from 110% to 1,000%, from 125% to 1,000%,from 200% to 900%, or from 300% to 900%). In other embodiments, thethrombi deposition on the potted bundle is reduced by at least 10%, 20%,40%, 60%, or 80% (e.g., from 10% to 95%, from 10% to 80%, from 20% to95%, from 35% to 85%, or from 40% to 80%) when contacted with blood. Instill other embodiments, the bundle has an operating pressure after 4hours of use that is reduced by at least 10%, 20%, 30%, 40%, or 50%(e.g., from 10% to 95%, from 10% to 80%, from 20% to 75%, from 25% to45%, or from 30% to 80%). In some embodiment, the potted bundle reducesadverse advents in a subject receiving blood passing through the pottedbundle. In other embodiments, the potting resin is antithrombogenic whencontacted with blood.

In one embodiment, the bundle of potted hollow fiber membranes within anencasement is part of a blood purification device (e.g., hemodialysis,hemodiafiltration, hemofiltration, hemoconcentration, or oxygenatordevice). In yet another embodiment, the potting resin is a cross-linkedpolyurethane (e.g., a cross-linked polyurethane formed from 4′-methylenebis(cyclohexyl isocyanate; 2,2′-methylene bis(phenyl)isocyanate;2,4′-methylene bis(phenyl)isocyanate; or 4,4′-methylenebis(phenyl)isocyanate).

In another aspect, the invention features a dialysis filter includingany hollow fiber membrane described herein or any potted bundledescribed herein, where the filter has a prolonged working life. In oneembodiment, the dialysis filter reduces adverse advents in a subjectreceiving blood passing through the dialysis filter.

In another aspect, the invention features a blood tubing including abase polymer (e.g., polyvinyl chloride) admixed with from 0.005% to 10%(w/w) (e.g., from 0.005% to 0.1% (w/w), from 0.005% to 5% (w/w), from0.1% to 0.3% (w/w), from 0.1% to 5% (w/w), from 0.1% to 10% (w/w), from0.05% to 5% (w/w), 0.05% to 8% (w/w), from 1% to 5% (w/w), from 1% to 8%(w/w), from 1% to 10% (w/w), and from 2% to 10% (w/w)) surface modifyingmacromolecule, where the blood tubing is antithrombogenic when contactedwith blood. In a particular embodiment, the base polymer includespolyvinyl chloride. In one embodiment, the blood tubing reduces adverseadvents in a subject receiving blood passing through the blood tubing.In one embodiment, the thrombi deposition at the surface of the bloodtubing is reduced by at least 10%, 20%, 40%, 60%, or 80% (e.g., from 10%to 95%, from 10% to 80%, from 20% to 95%, from 35% to 85%, or from 40%to 80%) when contacted with blood. In another embodiment, the bloodtubing has an increased average functional working life of at least110%, 125%, 150%, 200%, or 400% (e.g., from 110% to 1,000%, from 125% to1,000%, from 200% to 900%, or from 300% to 900%).

The invention further features method for treating a subject sufferingfrom impaired kidney function, the method including performing aprocedure selected from hemodialysis, hemofiltration, hemoconcentration,or hemodiafiltration on the subject using a dialysis filter, where thefilter includes any hollow fiber membrane described herein or any pottedbundle described herein. In one embodiment, during the procedure thesubject receives less than a standard dose of anticoagulant (e.g., whereduring the procedure the subject receives no anticoagulant). In anotherembodiment, the filter has a prolonged working life. In yet anotherembodiment, the filter has an increased average functional working lifeof at least 110%, 125%, 150%, 200%, or 400% (e.g., from 110% to 1,000%,from 125% to 1,000%, from 200% to 900%, or from 300% to 900%). In oneembodiment, the thrombi deposition on the filter is reduced by at least10%, 20%, 40%, 60%, or 80% (e.g., from 10% to 95%, from 10% to 80%, from20% to 95%, from 35% to 85%, or from 40% to 80%) when contacted withblood. In another embodiment, the filter has an operating pressure after4 hours of use that is reduced by at least 10%, 20%, 30%, 40%, or 50%(e.g., from 10% to 95%, from 10% to 80%, from 20% to 75%, from 25% to45%, or from 30% to 80%). In yet another embodiment, the adverse eventsexperienced by the subject are reduced.

The invention features a method for treating a subject suffering fromimpaired cardiac function, the method including performing a surgeryselected from a coronary artery bypass grafting and a cardiac valvereplacement using an oxygenator device, where the oxygenator deviceincludes any hollow fiber membrane described herein or any potted bundledescribed herein. In one embodiment, during the procedure the subjectreceives less than a standard dose of anticoagulant (e.g., where duringthe procedure the subject receives no anticoagulant). In anotherembodiment, the adverse events experienced by the subject are reduced.

The invention features a method for treating a subject, said methodincluding withdrawing blood from, and returning blood to, said subjectvia any extracorporeal blood circuit described herein. In oneembodiment, during the procedure the subject receives less than astandard dose of anticoagulant (e.g., where during the procedure thesubject receives no anticoagulant). In another embodiment, the adverseevents experienced by the subject are reduced.

The invention also features a method for purifying a protein in blood, ablood product (e.g., plasma or fractionated blood component), or acombination thereof, the method including dialyzing the blood, the bloodproduct, or the combination thereof across any hollow fiber membranedescribed herein or any potted bundle described herein.

The invention features a hollow fiber plasma purification membrane,including any bundle of potted hollow fiber membranes described herein.

The invention also features a spinning solution for preparing a hollowfiber membrane, the spinning solution including (i) from 57% to 87%(w/w) (e.g., from 57% to 85% (w/w), from 70% to 87% (w/w), and from 70%to 85% (w/w)) of an aprotic solvent; (ii) from 10% to 25% (w/w) (e.g.,from 10% to 20% (w/w), from 12% to 25% (w/w), and from 12% to 20% (w/w))of base polymer; (iii) from 0.005% to 8% (w/w) (e.g., from 0.005% to 5%(w/w), from 0.005% to 3% (w/w), 0.005% to 2% (w/w), from 0.01% to 3%(w/w), and from 0.01% to 2% (w/w)) of surface modifying macromolecule;and (iv) from 3% to 10% (w/w) (e.g., from 3% to 7% (w/w), from 3% to 5%(w/w), and from 5% to 10% (w/w)) of hydrophilic pore forming agent. Incertain embodiments, the aprotic solvent is selected fromdimethylformamide, dimethylsulfoxide, dimethylacetamide,N-methylpyrrolidone, and mixtures thereof. In other embodiments, theaprotic solvent further includes less than 25% (v/v) (i.e., from 1% to25% (v/v), 1% to 15% (v/v), or 5% to 20% (v/v)) of a low boiling solventselected from tetrahydrofuran, diethylether, methylethyl ketone,acetone, and mixtures thereof. In still other embodiments, thehydrophilic pore forming agent is polyvinylpyrrolidone. The spinningsolution can be processed as described herein to produce a hollow fibermembrane of the invention.

The invention features a method for making a hollow fiber membraneincluding the steps of: (a) preparing a homogeneous spinning solution ofthe invention; and (b) extruding the homogeneous spinning solution froman outer annular orifice of a tube-in-orifice spinneret into an aqueoussolution to form the hollow fiber membrane.

The invention also features a method of potting hollow fiber membranesincluding the steps of: (a) forming a bundle of hollow fiber membranes,the bundle of hollow fiber membranes having lumens, a first set of fiberends, and a second set of fiber ends; (b) placing the first set of fiberends and the second set of fiber ends in an uncured potting liquid; (c)curing the potting liquid to form a potting resin in which the hollowfiber membranes are potted; (d) cutting the potting resin and fiber endsto form a first wall in which the first set of fiber ends is potted anda second wall in which the second set of fiber ends is potted; and (e)heating the first wall and the second wall (i.e., heating to facilitatethe migration of surface modifying macromolecule to the surface of thewall), where the potting liquid includes from 0.005% to 10% (w/w) (e.g.,from 0.005% to 0.1% (w/w), from 0.005% to 5% (w/w), from 0.1% to 0.3%(w/w), from 0.1% to 5% (w/w), from 0.1% to 10% (w/w), from 0.05% to 5%(w/w), 0.05% to 8% (w/w), from 1% to 5% (w/w), from 1% to 8% (w/w), from1% to 10% (w/w), and from 2% to 10% (w/w)) surface modifyingmacromolecule.

The invention features a dialysis kit including (i) a hollow fibermembrane of the invention, a potted bundle of the invention, a dialysisfilter of the invention, and/or blood tubing of the invention; and (ii)instructions for performing dialysis on a subject receiving less than astandard dose of anticoagulant (e.g., receiving no anticoagulant).

In any of the hollow fiber membranes described herein, the surfacemodifying macromolecule is selected from VII-a, VIII-a, VIII-b, VIII-c,VIII-d, IX-a, X-a, X-b, XI-a, XI-b, XII-a, XII-b, XIII-a, XIII-b,XIII-c, XIII-d, XIV-a, and XIV-b.

In one embodiment, the potting resin includes a surface modifyingmacromolecule selected from VII-a, VIII-a, IX-a, XI-a, VIII-d, and XI-b.

In another embodiment, the blood tubing includes a surface modifyingmacromolecule selected from VII-a, XIV-a, and XIV-b.

In any of the extracorporeal blood circuits, hollow fiber membranes (orpotted bundles thereof or plasma purification membranes thereof),potting materials (e.g., potting resin or potting liquid), bloodtubings, dialysis filters, spinning solutions, methods, systems, andkits, the surface modifying macromolecule is described by any of theformulas(I)-(XIV) below.(1) F_(T)-(oligo)-F_(T)  (I)

wherein F_(T) is a polyfluoroorgano group and oligo is an oligomericsegment.

wherein

(i) F_(T) is a polyfluoroorgano group covalently attached to LinkB;

(ii) C is a chain terminating group;

(iii) Oligo is an oligomeric segment;

(iv) LinkB is a coupling segment; and

(v) a is an integer greater than 0.(3) F_(T)—[B-(oligo)]_(n)-B—F_(T)  (III)

wherein

(i) B includes a urethane;

(ii) oligo includes polypropylene oxide, polyethylene oxide, orpolytetramethylene oxide;

(iii) F_(T) is a polyfluoroorgano group; and

(iv) n is an integer from 1 to 10.(4) F_(T)—[B-A]_(n)-B—F_(T)  (IV)

wherein

(i) A is a soft segment including hydrogenated polybutadiene, poly (2,2dimethyl-1-3-propylcarbonate), polybutadiene, poly(diethyleneglycol)adipate, poly(hexamethylene carbonate),poly(ethylene-co-butylene), neopentyl glycol-ortho phthalic anhydridepolyester, diethylene glycol-ortho phthalic anhydride polyester,1,6-hexanediol-ortho phthalic anhydride polyester, or bisphenol Aethoxylate;

(ii) B is a hard segment including a urethane; and

(iii) F_(T) is a polyfluoroorfgano group, and

(iv) n is an integer from 1 to 10.

wherein

(i) A is a soft segment;

(ii) B is a hard segment including a isocyanurate trimer or biurettrimer;

(iii) each F_(T) is a polyfluoroorgano group; and

(iv) n is an integer between 0 to 10.(6) F_(T)—[B-(Oligo)]_(n)-B—F_(T)  (VII)

wherein

(i) Oligo is an oligomeric segment including polypropylene oxide,polyethylene oxide, or polytetramethyleneoxide and having a theoreticalmolecular weight of from 500 to 3,000 Daltons (e.g., from 500 to 2,000Daltons, from 1,000 to 2,000 Daltons, or from 1,000 to 3,000 Daltons);

(ii) B is a hard segment formed from an isocyanate dimer;

(iii) F_(T) is a polyfluoroorgano group; and

(iv) n is an integer from 1 to 10.

wherein

(i) A is an oligomeric segment including polypropylene oxide,polyethylene oxide, polytetramethyleneoxide, or mixtures thereof, andhaving a theoretical molecular weight of from 500 to 3,000 Daltons(e.g., from 500 to 2,000 Daltons, from 1,000 to 2,000 Daltons, or from1,000 to 3,000 Daltons);

(ii) B is a hard segment including an isocyanurate trimer or biurettrimer;

(iii) F_(T) is a polyfluoroorgano group; and

(iv) n is an integer from 0 to 10.(8) F_(T)—[B-(Oligo)]_(n)-B—F_(T)  (IX)

wherein

(i) Oligo is a polycarbonate polyol having a theoretical molecularweight of from 500 to 3,000 Daltons (e.g., from 500 to 2,000 Daltons,from 1,000 to 2,000 Daltons, or from 1,000 to 3,000 Daltons);

(ii) B is a hard segment formed from an isocyanate dimer;

(iii) F_(T) is a polyfluoroorgano group; and

(iv) n is an integer from 1 to 10.

wherein

(i) A is an oligomeric segment including a polycarbonate polyol having atheoretical molecular weight of from 500 to 3,000 Daltons (e.g., from500 to 2,000 Daltons, from 1,000 to 2,000 Daltons, or from 1,000 to3,000 Daltons);

(ii) B is a hard segment including an isocyanurate trimer or biurettrimer;

(iii) F_(T) is a polyfluoroorgano group; and

(iv) n is an integer from 0 to 10.

wherein

(i) A includes a first block segment selected from polypropylene oxide,polyethylene oxide, polytetramethyleneoxide, or mixtures thereof, and asecond block segment including a polysiloxane or polydimethylsiloxane,wherein A has a theoretical molecular weight of from 1,000 to 5,000Daltons (e.g., from 1,000 to 3,000 Daltons, from 2,000 to 5,000 Daltons,or from 2,500 to 5,000 Daltons);

(ii) B is a hard segment including an isocyanurate trimer or biurettrimer;

(iii) F_(T) is a polyfluoroorgano group; and

(iv) n is an integer from 0 to 10.(11) F_(T)—[B-A]_(n)-B—F_(T)  (XII)

wherein

(i) A is a soft segment selected from hydrogenated polybutadiene (HLBH)diol (e.g., HLBH diol), polybutadiene (LBHP) diol (e.g., LBHP diol),hydrogenated polyisoprene (HHTPI) diol (e.g., HHTPI diol), andpolystyrene and has a theoretical molecular weight of from 750 to 3,500Daltons (e.g., from 750 to 2,000 Daltons, from 1,000 to 2,500 Daltons,or from 1,000 to 3,500 Daltons);

(ii) B is a hard segment formed from an isocyanate dimer;

(iii) F_(T) is a polyfluoroorgano group; and

(iv) n is an integer from 1 to 10.

wherein

(i) A is a soft segment selected from hydrogenated polybutadiene (HLBH)diol (e.g., HLBH diol), polybutadiene (LBHP) diol (e.g., LBHP diol),hydrogenated polyisoprene (HHTPI) diol (e.g., HHTPI diol), andpolystyrene and has a theoretical molecular weight of from 750 to 3,500Daltons (e.g., from 750 to 2,000 Daltons, from 1,000 to 2,500 Daltons,or from 1,000 to 3,500 Daltons);

(ii) B is a hard segment including an isocyanurate trimer or biurettrimer;

(iii) F_(T) is a polyfluoroorgano group; and

(iv) n is an integer from 0 to 10.

wherein

(i) A is a polyester having a theoretical molecular weight of from 500to 3,500 Daltons (e.g., from 500 to 2,000 Daltons, from 1,000 to 2,000Daltons, or from 1,000 to 3,000 Daltons);

(ii) B is a hard segment including an isocyanurate trimer or biurettrimer;

(iii) F_(T) is a polyfluoroorgano group; and

(iv) n is an integer from 0 to 10.

In certain embodiments, the surface modifying macromolecule of formulas(I) and (II) include an oligo segment that is a branched or non-branchedoligomeric segment of fewer than 20 repeating units (e.g., from 2 to 15units, from 2 to 10 units, from 3 to 15 units, and from 3 to 10 units).In another embodiment, the surface modifying macromolecule of formulas(I) and (II) include an oligomeric segment selected from polyurethane,polyurea, polyamide, polyalkylene oxide, polycarbonate, polyester,polylactone, polysilicone, polyethersulfone, polyolefin, polyvinylderivative, polypeptide, polysaccharide, polysiloxane,polydimethylsiloxane, polyethylene-butylene, polyisobutylene,polybutadiene, polypropylene oxide, polyethylene oxide,polytetramethylene oxide, or polyethylenebutylene segments.

In certain embodiments, the surface modifying macromolecule of formulas(IV) include a hard segment formed from a diisocyanate selected from3-isocyanatomethyl, 3,5,5-trimethyl cyclohexylisocyanate; 4,4′-methylenebis(cyclohexyl isocyanate); 4,4′-methylene bis(phenyl) isocyanate;toluene-2,4 diisocyanate); m-tetramethylxylene diisocyanate; andhexamethylene diisocyanate; and n is 1 or 2.

In certain embodiments, the surface modifying macromolecule of formulas(V) and (VI) include a soft segment having a theoretical molecularweight of 500 to 3,500 Daltons (e.g., from 500 to 2,000 Daltons, from1,000 to 2,000 Daltons, or from 1,000 to 3,000 Daltons) and/or the softsegment includes hydrogenated polybutadiene (HLBH), poly (2,2dimethyl-1-3-propylcarbonate) (PCN), polybutadiene (LBHP),polytetramethylene oxide (PTMO), (propylene) oxide (PPO),diethyleneglycol-orthophthalic anhydride polyester (PDP), hydrogenatedpolyisoprene (HHTPI), poly(hexamethylene carbonate),poly(2-butyl-2-ethyl-1,3- propyl carbonate),or hydroxylterminatedpolydimethylsiloxane (C22). In other embodiments of the surfacemodifying macromolecule of formulas (V) and (VI), the hard segment isformed by reacting a triisocyanate with a diol including the softsegment, wherein the triisocyanate is selected from hexamethylenediisocyanate (HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer,or hexamethylene diisocyanate (HDI) trimer.

In some embodiments of the surface modifying macromolecule of formula(VII), B is a hard segment formed from 3-isocyanatomethyl,3,5,5-trimethyl cyclohexylisocyanate; 4,4′-methylene bis(cyclohexylisocyanate); 4,4′-methylene bis(phenyl) isocyanate; toluene-2,4diisocyanate); m-tetramethylxylene diisocyanate; and hexamethylenediisocyanate; and n is an integer from 1 to 3. In one particularembodiment, the surface modifying macromolecule of formula (VII) isVII-a. The surface modifying macromolecules of formula (VII) can be usedin an extracorporeal blood circuit of the invention, or a componentthereof, such as a hollow fiber membrane, potted bundle, blood tubing,or dialysis filter, and in conjunction with any methods, systems, andkits of the invention described herein. For example, the surfacemodifying macromolecules of formula (VII) can be added to polyvinylchloride to make an antithrombogenic blood tubing; added to a pottingmaterial to make an antithrombogenic potted bundle; and/or added to thebase polymer of a hollow fiber membrane (e.g., a polysulfone, apolyacrylonitrile, a cellulose acetate, a cellulose di-or tri-acetate, apolyimide, a poly(methyl methacrylate), a polycarbonate, a polyamide, apolypropylene, or a polyethylene) to form a hollow fiber membrane thatis antithrombogenic when contacted with blood.

In certain embodiments of the surface modifying macromolecule of formula(VIII), B is a hard segment formed by reacting a triisocyanate with adiol of A (e.g., the oligomeric segment), wherein the triisocyanate isselected from hexamethylene diisocyanate (HDI) biuret trimer, isophoronediisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer;and n is 0, 1, 2, or 3. In one particular embodiment, the surfacemodifying macromolecule of formula (VIII) is VIII-a, VIII-b, VIII-c, orVIII-d. The surface modifying macromolecules of formula (VIII) can beused in an extracorporeal blood circuit of the invention, or a componentthereof, such as a hollow fiber membrane, potted bundle, blood tubing,or dialysis filter, and in conjunction with any methods, systems, andkits of the invention described herein. For example, the surfacemodifying macromolecules of formula (VIII) can be added to polyvinylchloride to make an antithrombogenic blood tubing; added to a pottingmaterial to make an antithrombogenic potted bundle; and/or added to thebase polymer of a hollow fiber membrane (e.g., a polysulfone, apolyacrylonitrile, a cellulose acetate, a cellulose di-or tri-acetate, apolyimide, a poly(methyl methacrylate), a polycarbonate, a polyamide, apolypropylene, or a polyethylene) to form a hollow fiber membrane thatis antithrombogenic when contacted with blood.

In certain embodiments of the surface modifying macromolecule of formula(IX), Oligo includes poly (2,2 dimethyl-1-3-propylcarbonate) (PCN)polyol (e.g., PCN diol); B is a hard segment formed from3-isocyanatomethyl, 3,5,5-trimethyl cyclohexylisocyanate; 4,4′-methylenebis(cyclohexyl isocyanate); 4,4′-methylene bis(phenyl) isocyanate;toluene-2,4 diisocyanate); m-tetramethylxylene diisocyanate; andhexamethylene diisocyanate; and n is 1, 2, or 3. In one particularembodiment, the surface modifying macromolecule of formula (IX) is IX-a.The surface modifying macromolecules of formula (IX) can be used in anextracorporeal blood circuit of the invention, or a component thereof,such as a hollow fiber membrane, potted bundle, blood tubing, ordialysis filter, and in conjunction with any methods, systems, and kitsof the invention described herein. For example, the surface modifyingmacromolecules of formula (IX) can be added to polyvinyl chloride tomake an antithrombogenic blood tubing; added to a potting material tomake an antithrombogenic potted bundle; and/or added to the base polymerof a hollow fiber membrane (e.g., a polysulfone, a polyacrylonitrile, acellulose acetate, a cellulose di-or tri-acetate, a polyimide, apoly(methyl methacrylate), a polycarbonate, a polyamide, apolypropylene, or a polyethylene) to form a hollow fiber membrane thatis antithrombogenic when contacted with blood.

In certain embodiments of the surface modifying macromolecule of formula(X), A includes poly(2,2 dimethyl-1-3-propylcarbonate) (PCN) polyol(e.g., PCN diol) or poly(hexamethylene carbonate) (PHCN) polyol; B is ahard segment formed by reacting a triisocyanate with a diol of A (e.g.,the oligomeric segment), wherein the triisocyanate is selected fromhexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate(IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer; and n is 0,1, 2, or 3. In one particular embodiment, the surface modifyingmacromolecule of formula (X) is X-a or X-b. The surface modifyingmacromolecules of formula (X) can be used in an extracorporeal bloodcircuit of the invention, or a component thereof, such as a hollow fibermembrane, potted bundle, blood tubing, or dialysis filter, and inconjunction with any methods, systems, and kits of the inventiondescribed herein. For example, the surface modifying macromolecules offormula (X) can be added to polyvinyl chloride to make anantithrombogenic blood tubing; added to a potting material to make anantithrombogenic potted bundle; and/or added to the base polymer of ahollow fiber membrane (e.g., a polysulfone, a polyacrylonitrile, acellulose acetate, a cellulose di- or tri-acetate, a polyimide, apoly(methyl methacrylate), a polycarbonate, a polyamide, apolypropylene, or a polyethylene) to form a hollow fiber membrane thatis antithrombogenic when contacted with blood.

In certain embodiments of the surface modifying macromolecule of formula(XI), A is a includes polypropylene oxide and polydimethylsiloxane; B isa hard segment formed by reacting a triisocyanate with a diol of A,wherein the triisocyanate is selected from hexamethylene diisocyanate(HDI) biuret trimer, isophorone diisocyanate (IPDI) trimer, andhexamethylene diisocyanate (HDI) trimer; and n is 0, 1, 2, or 3. In oneparticular embodiment, the surface modifying macromolecule of formula(XI) is XI-a or XI-b. The surface modifying macromolecules of formula(XI) can be used in an extracorporeal blood circuit of the invention, ora component thereof, such as a hollow fiber membrane, potted bundle,blood tubing, or dialysis filter, and in conjunction with any methods,systems, and kits of the invention described herein. For example, thesurface modifying macromolecules of formula (XI) can be added topolyvinyl chloride to make an antithrombogenic blood tubing; added to apotting material to make an antithrombogenic potted bundle; and/or addedto the base polymer of a hollow fiber membrane (e.g., a polysulfone, apolyacrylonitrile, a cellulose acetate, a cellulose di- or tri-acetate,a polyimide, a poly(methyl methacrylate), a polycarbonate, a polyamide,a polypropylene, or a polyethylene) to form a hollow fiber membrane thatis antithrombogenic when contacted with blood.

In certain embodiments of the surface modifying macromolecule of formula(XII), A includes hydrogenated polybutadiene diol; B is a hard segmentformed from 3-isocyanatomethyl, 3,5,5-trimethyl cyclohexylisocyanate;4,4′methylene bis(cyclohexyl isocyanate); 4,4′-methylene bis(phenyl)isocyanate; toluene-2,4 diisocyanate); m-tetramethylxylene diisocyanate;and hexamethylene diisocyanate; and n is 1, 2, or 3. In one particularembodiment, the surface modifying macromolecule of formula (XII) isXII-a or XII-b. The surface modifying macromolecules of formula (XII)can be used in an extracorporeal blood circuit of the invention, or acomponent thereof, such as a hollow fiber membrane, potted bundle, bloodtubing, or dialysis filter, and in conjunction with any methods,systems, and kits of the invention described herein. For example, thesurface modifying macromolecules of formula (XII) can be added topolyvinyl chloride to make an antithrombogenic blood tubing; added to apotting material to make an antithrombogenic potted bundle; and/or addedto the base polymer of a hollow fiber membrane (e.g., a polysulfone, apolyacrylonitrile, a cellulose acetate, a cellulose di- or tri-acetate,a polyimide, a poly(methyl methacrylate), a polycarbonate, a polyamide,a polypropylene, or a polyethylene) to form a hollow fiber membrane thatis antithrombogenic when contacted with blood.

In certain embodiments of the surface modifying macromolecule of formula(XIII), A is selected from hydrogenated polybutadiene (HLBH) diol (e.g.,HLBH diol), and hydrogenated polyisoprene (HHTPI) diol (e.g., HHTPIdiol); B is a hard segment formed by reacting a triisocyanate with adiol of A (e.g., the oligomeric segment), wherein the triisocyanate isselected from hexamethylene diisocyanate (HDI) biuret trimer, isophoronediisocyanate (IPDI) trimer, and hexamethylene diisocyanate (HDI) trimer;and n is 0, 1, 2, or 3. In one particular embodiment, the surfacemodifying macromolecule of formula (XIII) is XIII-a, XIII-b, XIII-c, orXIII-d The surface modifying macromolecules of formula (XIII) can beused in an extracorporeal blood circuit of the invention, or a componentthereof, such as a hollow fiber membrane, potted bundle, blood tubing,or dialysis filter, and in conjunction with any methods, systems, andkits of the invention described herein. For example, the surfacemodifying macromolecules of formula (XIII) can be added to polyvinylchloride to make an antithrombogenic blood tubing; added to a pottingmaterial to make an antithrombogenic potted bundle; and/or added to thebase polymer of a hollow fiber membrane (e.g., a polysulfone, apolyacrylonitrile, a cellulose acetate, a cellulose di- or tri-acetate,a polyimide, a poly(methyl methacrylate), a polycarbonate, a polyamide,a polypropylene, or a polyethylene) to form a hollow fiber membrane thatis antithrombogenic when contacted with blood.

In certain embodiments of the surface modifying macromolecule of formula(XIV), A is selected from poly (diethylene glycol)adipate, neopentylglycol-ortho phthalic anhydride polyester, diethylene glycol-orthophthalic anhydride polyester, and 1,6-hexanediol-ortho phthalicanhydride polyester; B is a hard segment formed by reacting atriisocyanate with a diol of A (e.g., the polyester segment), whereinthe triisocyanate is selected from hexamethylene diisocyanate (HDI)biuret trimer, isophorone diisocyanate (IPDI) trimer, and hexamethylenediisocyanate (HDI) trimer; and n is 0, 1, 2, or 3. In one particularembodiment, the surface modifying macromolecule of formula (XIV) isXIV-a or XIV-b. The surface modifying macromolecules of formula (XIV)can be used in an extracorporeal blood circuit of the invention, or acomponent thereof, such as a hollow fiber membrane, potted bundle, bloodtubing, or dialysis filter, and in conjunction with any methods,systems, and kits of the invention described herein. For example, thesurface modifying macromolecules of formula (XIV) can be added topolyvinyl chloride to make an antithrombogenic blood tubing; added to apotting material to make an antithrombogenic potted bundle; and/or addedto the base polymer of a hollow fiber membrane (e.g., a polysulfone, apolyacrylonitrile, a cellulose acetate, a cellulose di- or tri-acetate,a polyimide, a poly(methyl methacrylate), a polycarbonate, a polyamide,a polypropylene, or a polyethylene) to form a hollow fiber membrane thatis antithrombogenic when contacted with blood.

For any of the surface modifying macromolecules of the invention formedfrom an isocyanate dimer, the isocyanate dimers can be selected from3-isocyanatomethyl, 3,5,5-trimethyl cyclohexylisocyanate; 4,4′-methylenebis(cyclohexyl isocyanate) (HMDI); 2,2′-, 2,4′-, and 4,4′-methylenebis(phenyl) isocyanate (MDI); toluene-2,4 diisocyanate; aromaticaliphatic isocyanate, such 1,2-, 1,3-, and 1,4-xylene diisocyanate;meta-tetramethylxylene diisocyanate (m-TMXDI); para-tetramethylxylenediisocyanate (p-TMXDI); hexamethylene diisocyanate (HDI); ethylenediisocyanate; propylene-1,2-diisocyanate; tetramethylene diisocyanate;tetramethylene-1,4-diisocyanate; octamethylene diisocyanate;decamethylene diisocyanate; 2,2,4-trimethylhexamethylene diisocyanate;2,4,4-trimethylhexamethylene diisocyanate; dodecane-1,12-diisocyanate;dicyclohexylmethane diisocyanate; cyclobutane-1,3-diisocyanate;cyclohexane-1,2-diisocyanate; cyclohexane-1,3-diisocyanate;cyclohexane-1,4-diisocyanate; methyl-cyclohexylene diisocyanate (HTDI);2,4-methylcyclohexane diisocyanate; 2,6-methylcyclohexane diisocyanate;4,4′-dicyclohexyl diisocyanate; 2,4′-dicyclohexyl diisocyanate;1,3,5-cyclohexane triisocyanate; isocyanatomethylcyclohexane isocyanate;1-isocyanato-3,3-5-trimethyl-5-isocyanatomethylcyclohexane;isocyanatoethylcyclohexane isocyanate; bis(isocyanatomethyl)-cyclohexanediisocyanate; 4,4′-bis(isocyanatomethyl) dicyclohexane;2,4′-bis(isocyanatomethyl)dicyclohexane; isophoronediisocyanate (IPDI);2,4-hexahydrotoluene diisocyanate; 2,6-hexahydrotoluenediisocyanate;3,3′-dimethyl-4,4′-biphenylene diisocyanate (TODI);polymeric MDI; carbodiimide-modified liquid 4,4′-diphenylmethanediisocyanate; para-phenylene diisocyanate (PPDI); meta-phenylenediisocyanate (MPDI); triphenyl methane-4,4′-, and triphenylmethane-4,4″-triisocyanate; naphthylene-1,5-diisocyanate; 2,4′-, 4,4′-,and 2,2-biphenyl diisocyanate; polyphenyl polymethylene polyisocyanate(PMDI); mixtures of MDI and PMDI; mixtures of PMDI and TDI; dimerizeduredione of any isocyanate described herein, such as uredione of toluenediisocyanate, uredione of hexamethylene diisocyanate, and mixturesthereof; and substituted and isomeric mixtures thereof.

For any of the surface modifying macromolecules of the invention formedfrom an isocyanate trimer, the isocyanate trimer can be selected fromhexamethylene diisocyanate (HDI) biuret trimer, isophorone diisocyanate(IPDI) trimer, hexamethylene diisocyanate (HDI) trimer; triisocyanate of2,2,4-trimethyl-1,6-hexane diisocyanate (TMDI); a trimerizedisocyanurate of any isocyanates described herein, such as isocyanurateof toluene diisocyanate, trimer of diphenylmethane diisocyanate, trimerof tetramethylxylene diisocyanate, and mixtures thereof; a trimerizedbiuret of any isocyanates described herein; modified isocyanates derivedfrom the above diisocyanates; and substituted and isomeric mixturesthereof.

In any of formulas (I)-(XIV), the above surface modifying macromoleculeincludes the group F_(T) that is a polyfluoroalkyl having a theoreticalmolecular weight of between 100-1,500 Da. For example, F_(T) may beselected from the group consisting of radicals of the general formulaCF₃(CF₂)_(r)CH₂CH₂— wherein r is 2-20, and CF₃(CF₂)_(s)(CH₂CH₂O)_(χ)wherein χ is 1-10 and s is 1-20. Alternatively, F_(T) may be selectedfrom the group consisting of radicals of the general formulaCH_(m)F(_(3-m))(CF₂)_(r)CH₂CH₂— andCH_(m)F(_(3-m))(CF₂)_(s)(CH₂CH₂O)_(χ)-, wherein m is 0, 1, 2, or 3; χ isan integer between 1-10; r is an integer between 2-20; and s is aninteger between 1-20. In certain embodiments, F_(T) is selected from1H,1H,2H,2H-perfluoro-1-decanol; 1H,1H,2H,2H-perfluoro-1-octanol;1H,1H,5H-perfluoro-1-pentanol; and 1H,1H, perfluoro-1-butanol, andmixtures thereof. In still other embodiments, F_(T) is selected from(CF₃)(CF₂)₅CH₂CH₂O—, (CF₃)(CF₂)₇CH₂CH₂O—, (CF₃)(CF₂)₅CH₂CH₂O—,CHF₂(CF₂)₃CH₂O—, and (CF₃)(CF₂)₂CH₂O—.

In another embodiment, the above surface modifying macromolecule has atheoretical molecular weight of less than 10,000 Daltons (e.g., from 500to 10,000 Daltons, from 500 to 9,000 Daltons, from 500 to 5,000 Daltons,from 1,000 to 10,000 Daltons, from 1,000 to 6,000 Daltons, or from 1,500to 8,000 Daltons).

In still another embodiment, the above surface modifying macromoleculeincludes from 5% to 40% (w/w) of the hard segment (e.g., from 5% to 35%(w/w), from 5% to 30% (w/w), and from 10% to 40% (w/w)), from 20% to 90%(w/w) of the soft segment (e.g., from 20% to 80% (w/w), from 30% to 90%(w/w), and from 40% to 90% (w/w)), and from 5% to 50% (w/w) of thepolyfluoroorgano group (e.g., from 5% to 40% (w/w), from 5% to 30%(w/w), and from 10% to 40% (w/w)).

In one embodiment, the above surface modifying macromolecule has a ratioof hard segment to soft segment of from 0.15 to 2.0 (e.g., from 0.15 to1.8, from 0.15 to 1.5, and from 0.2 to 2.0).

As used herein, the term “antithrombogenic” refers to an extracorporealblood circuit, or component thereof (e.g., a hollow fiber membrane,blood tubing, dialysis filter, and/or a potted bundle of hollow fibermembranes) for which the rate at which thrombosis occurs upon exposureto whole blood under is reduced in comparison to an otherwise identicalextracorporeal blood circuit, or component thereof, that differs only bythe absence of a surface modifying macromolecule tested under the sameblood-contacting conditions. A reduced rate of thrombosis can bedetermined by any of the assays and methods described herein. Forexample, antithrombogenicity can be determined by radiolabeling bloodcomponents and measuring the formation of thrombi using, for example, aγ-count to assess the amount of thrombosis occurring at a surface. Forthe extracorporeal blood circuits, or components thereof, of theinvention an average decrease in thrombosis based upon the γ-count canbe 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the average thrombosis asdetermined by γ-count of a reference hollow fiber membrane lacking thesurface modifying macromolecule). Alternatively, antithrombogenicity ina filter or hollow fiber membrane can be determined by a reducedoperating pressure (e.g., an average decrease in operating pressure atthe header of a hollow fiber membrane being reduced by at least 10%,20%, 30%, 40%, 50%, or 60% in comparison to the average pressure at theheader of a reference filter or hollow fiber membrane lacking thesurface modifying macromolecule.

By “base polymer” is meant a polymer having a theoretical molecularweight of greater than 50,000 Daltons (e.g., greater than 50,000,75,000, 100,000, 150,000, 200,000 Daltons).

As used herein, “C” refers to a chain terminating group. Exemplary chainterminating groups include monofunctional groups containing an amine,alcohol, or carboxylic acid functionality.

By “dialysis filter” is meant a filter configured for use in a dialysismachine which can be used by patients suffering from impaired kidneyfunction.

By “hard segment” is meant a portion of the surface modifyingmacromolecule or a portion of an oligo segment, where the portionincludes a urethane group —NH—C(O)O— (e.g., a urethane group formed byreacting an isocyanate with a hydroxyl group of a soft segment diol or ahydroxyl group of a polyfluoroorgano group).

As used herein, the term “increased average functional working life”refers to an average increase in functional working life for anextracorporeal blood circuit, or component thereof, of the invention incomparison to the average working life of an extracorporeal bloodcircuit, or component thereof, used under the same conditions anddiffering only by the absence of surface modifying macromolecule, wherethe working life is determined by the length of time the extracorporealcircuit, or a component thereof, can be used without having to flushthrombi deposits from the extracorporeal circuit, or a component thereof(e.g., working life without a saline flush, or flush with ananticoagulant). The increased average functional working life for anextracorporeal blood circuit, or component thereof, of the invention canbe at least 110%, 125%, 150%, 200%, 250%, 300%, or 400% longer than theworking life of the reference extracorporeal blood circuit, or componentthereof, lacking the surface modifying macromolecule.

By “less than a standard dose of anticoagulant” is meant a reduction inthe anticoagulant administered to a subject during hemodialysis whenusing the dialysis filters of the invention in comparison to the amountused for a dialysis filter that differs only by the absence of a surfacemodifying macromolecule. A standard dose is generally identified by eachinstitution in a standard operating procedure for a clinical setting,such as for use of an extracorporeal blood circuit, and componentsthereof. The standard dose of anticoagulant refers to a dose or a rangeof doses determined by reference to a standard operating procedure of aninstitution, and a reduced dose is determined as compared to thatstandard dose. The reduced dose of anticoagulant can be 80%, 70%, 60%,50%, 40%, 30%, 20%, or 10% of the standard dose of anticoagulant (e.g.,heparin or citrate).

As used herein, “LinkB” refers to a coupling segment capable ofcovalently linking two oligo moieties and a surface active group.Typically, LinkB molecules have molecular weights ranging from 40 to700. Preferably the LinkB molecules are selected from the group offunctionalized diamines, diisocyanates, disulfonic acids, dicarboxylicacids, diacid chlorides and dialdehydes, wherein the functionalizedcomponent has secondary functional chemistry that is accessed forchemical attachment of a surface active group. Such secondary groupsinclude, for example, esters, carboxylic acid salts, sulfonic acidsalts, phosphonic acid salts, thiols, vinyls and secondary amines.Terminal hydroxyls, amines or carboxylic acids on the oligointermediates can react with diamines to form oligo-amides; react withdiisocyanates to form oligo-urethanes, oligo-ureas, oligo-amides; reactwith disulfonic acids to form oligo-sulfonates, oligo-sulfonamides;react with dicarboxylic acids to form oligo-esters, oligo-amides; reactwith diacid chlorides to form oligo-esters, oligo-amides; and react withdialdehydes to form oligo-acetal, oligo-imines.

By “oligo” is meant a relatively short length of a repeating unit orunits, generally less than about 50 monomeric units and theoreticalmolecular weights less than 10,000 Daltons, but preferably <7,000Daltons and in some examples, <5,000 Daltons. In certain embodiments,oligo is selected from the group consisting of polyurethane, polyurea,polyamide, polyalkylene oxide, polycarbonate, polyester, polylactone,polysilicone, polyethersulfone, polyolefin, polyvinyl, polypeptide,polysaccharide, and ether and amine linked segments thereof.

By “polyethersulfone” is meant a polymer of the formula:

This polymer is commercially available under the trade name Radel™ fromAmoco Corp.

By “polymeric component” is meant any component within an extracorporealblood circuit, wherein the component includes a base polymer, asdescribed herein. For example, polymeric components include a hollowfiber membrane, a potted bundle of hollow fiber membranes, a dialysisfilter, an oxygenator device, and a blood tubing.

By “poly(oxy-1,4-phenylenesulfonyl-1,4-phenyleneoxy-1,4-phenyleneisopropylidene-1,4-phenylene)” ismeant a polymer of the formula:

This polymer is commercially available under the trade name Udel™ P-3500from Solvay Advanced Polymers. For use in the hollow fiber membranes ofthe invention, a particular size for this polymer may be preferred(i.e., in the range of 30-90 kDa; 45-80 kDa; or 60-80 kDa.).

As used herein, the term “polysulfone” refers to a class of polymersthat include as a repeating subunit the moiety -aryl-SO₂-aryl-.Polysulfones include, without limitation, polyethersulfones andpoly(oxy-1,4-phenylenesulfonyl-1,4-phenyleneoxy-1,4-phenyleneisopropylidene-1,4-phenylene).

By “prolonged working life” is meant a dialysis filter for which therate at which the filter becomes clogged during a hemodialysis procedure(e.g., and then requiring a saline flush to unclog the filter), isreduced in comparison to a dialysis filter that differs only by theabsence of a surface modifying macromolecule used under the sameconditions. The prolonged working life for a dialysis filter can be atleast 110%, 125%, 150%, 200%, 250%, 300%, or 400% longer than theworking life of the reference dialysis filter lacking the surfacemodifying macromolecule.

As used herein, the term “reduced thrombi deposition” refers to anaverage decrease in γ-count following a period of use (e.g., 60, 90,120, 360, or 720 minutes), for an extracorporeal blood circuit, orcomponent thereof, of the invention in comparison to the average γ-countobserved for an extracorporeal blood circuit used under the sameconditions and differing only by the absence of surface modifyingmacromolecule. The γ-count is obtained by incorporating surfacemodifying macromolecule into the extracorporeal blood circuit to providean antithrombogenic interface between the membrane and the flow of bloodpassing through the membrane, where γ-count is measured at any treatedsurface of the circuit and is measured under conditions in which theamount of anticoagulant included in the blood is insufficient to preventthe formation of thrombi in the absence of surface modifyingmacromolecule. A γ-count can be determined by any of the assays andmethods described herein. For example, γ-count can be determined byflowing blood or plasma containing radiolabeled platelets (or otherblood components, such as red blood cells) into an extracorporeal bloodcircuit and measuring the radiation from the radiolabel within theextracorporeal blood circuit. These assays and methods can be performedmultiple times to obtain an average γ-count or an average decrease inγ-count. The thrombi deposition for an extracorporeal blood circuit, orcomponent thereof, of the invention can be on average reduced by 10%,20%, 30, 40%, 50%, 60%, 70%, 80%, 90%, or 95% in comparison to theaverage thrombi deposition of the extracorporeal blood circuit, orcomponent thereof, lacking the surface modifying macromolecule.

By “reduced operating pressure” is meant an average decrease inoperating pressure following a period of use (e.g., 2 hrs, 4 hrs, 8 hrs,12 hrs, or 16 hrs), for a hollow fiber membrane, or filters or pottedbundles thereof, of the invention in comparison to the average pressureobserved for a hollow fiber membrane used under the same conditions anddiffering only by the absence of surface modifying macromolecule. Thereduced operating pressure is obtained by incorporating surfacemodifying macromolecule into the hollow fiber membrane to provide anantithrombogenic interface between the membrane and the flow of bloodpassing through the membrane, where pressure is measured at the headerof the membrane. For an array of hollow fiber membranes having a pottingresin at an end of the array, a reduced operating pressure can beobtained by using a surface modifying macromolecule to provide anantithrombogenic interface between the membrane and/or the potting resinand the flow of blood passing through the potted bundle. Operatingpressure can be determined by any of the assays and methods describedherein. For example, operating pressure can be determined by flowingblood into a hollow fiber membrane and measuring the change in pressurewithin the hollow fiber membrane over a period of time. These assays andmethods can be performed multiple times to obtain an average operatingpressure or an average decrease in operating pressure. The reducedoperating pressure for a hollow fiber membrane (or filters or pottedbundles thereof) of the invention can be less than 10%, 20%, 30%, 40%,50%, 60%, 70%, or 80% after 2, 4, 8, 12, or 16 hours of use incomparison to the average pressure observed for a reference hollow fibermembrane, filter, or potted bundle lacking the surface modifyingmacromolecule.

As used herein, the terms “reduces adverse events” and “adverse eventsexperienced by a subject” refer to a number or extent of adverse eventsexperienced by a subject connected to an extracorporeal blood circuit,or component thereof, of the invention, where such adverse events arereduced or decreased during or after a period of use, in comparison toan extracorporeal blood circuit, or component, used under the sameconditions and differing only by the absence of surface modifyingmacromolecule. The number or extent of adverse events can be determinedby any useful method, including the use of animal models (see Livigni etal., Critical Care 10:R151 (2006); Walker et al., Artificial Organs8:329-333 (1984); Cheung, Blood Purification 5:155-161 (1987); Kamler etal., Journal of Thoracic and Cardiovascular Surgery 49:157-161 (2001);and Kamler et al., European Journal of Cardio-Thoracic Surgery11:973-980 (1997)). Adverse events include bleeding (e.g., measured bythe activated clotting time), hemolysis, reduced blood cell counts,severe hemodynamic instability, embolism, thromboembolism, athrombi-related event, and any other event requiring that the subjecttake an erythropoiesis-stimulating agent (e.g., erythropoietin and/orintravenous iron). The presence of one or more adverse events can beindicative of the presence of thrombi or the activation of bloodcomplements in the coagulation cascade.

By “soft segment” is meant a portion of the surface modifyingmacromolecule or a portion of an oligo segment, where the portionincludes an ether group, an ester group (e.g., a polyester), an alkylgroup, a carbonate group, a siloxane group, or a mixture thereof. Forexample, the soft segment can have a theoretical molecular weight oraverage molecular weight from 500 to 3,000 Daltons (e.g., from 500 to2,000 Daltons, from 1,000 to 2,000 Daltons, or from 1,000 to 3,000Daltons).

As used herein, “surface modifying macromolecule” refers to themacromolecules containing polyfluoroorgano groups and described hereinby formulas (I)-(XIV) and in U.S. Pat. No. 6,127,507; in U.S. PatentPublication No. 20080228253; and in U.S. Provisional Ser. No.61/092,667, filed Aug. 28, 2008, each of which is incorporated herein byreference. Surface modifying macromolecules can be prepared as describedin U.S. Pat. No. 6,127,507; U.S. Patent Publication No. 20080228253; andPCT Publication No. WO/2010/025398, filed Aug. 28, 2009. Briefly,surface modifying macromolecules, such as XI-a and X-a, may besynthesized from a polyisocyanate (e.g., Desmodur N3200 or DesmodurZ4470) reacted dropwise with a fluoroalkyl alcohol in an organic solvent(e.g., anhydrous THF or DMAC) in the presence of a catalyst at 25° C.for 2 hours. After addition of the fluorinated alcohol, stirring iscontinued for 1 hour at 50° C. and for a further 1 hour at 70° C. Thesesteps lead to the formation of a partially fluorinated intermediatewhich is then coupled with a polyol soft segment (e.g.,polydimethylsiloxane diol or poly(2,2 dimethyl-1-3- propyl carbonate)diol) at 70° C. over a period of 14 hours to provide the surfacemodifying macromolecule. Because the reactions are moisture sensitive,they are typically carried out under an inert N₂ atmosphere and underanhydrous conditions. The reaction product is precipitated in 1%MeOH/water mixture and then washed several times with water, and thesurface modifying macromolecule is dried prior to use. The soft segmentof the surface modifying macromolecule can function as an anchor for thesurface modifying macromolecule within the base polymer substrate uponadmixture. The surface active groups are responsible, in part, forcarrying the surface modifying macromolecule to the surface of theadmixture, where the surface active groups are exposed on the surface.The migration of the surface modifying macromolecules to the surface isa dynamic process and is dependent on the surface environment. Theprocess of migration is driven by the tendency towards establishing alow surface energy at the mixture's surface. When the balance betweenanchoring and surface migration is achieved, the surface modifyingmacromolecule remains stable at the surface of the polymer, whilesimultaneously altering surface properties.

This invention features blood circuits which can be useful for reducingplatelet adhesion, reducing occlusion, reducing the need for heparinand/or other anticoagulants, reducing the costs associated with certainmedical procedures, such as dialysis, prolonging the working life of theblood circuit, improving patient safety, and reducing waste.

Other features and advantages of the invention will be apparent from theDrawings, Detailed Description, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of an exemplary extracorporeal blood circuit.

FIG. 2 is an illustration depicting surface modifying macromoleculeVII-a of the invention.

FIG. 3 is an illustration depicting surface modifying macromoleculeVIII-a of the invention.

FIG. 4 is an illustration depicting surface modifying macromoleculeVIII-b of the invention.

FIG. 5 is an illustration depicting surface modifying macromoleculeVIII-c of the invention.

FIG. 6 is an illustration depicting surface modifying macromoleculeVIII-d of the invention.

FIG. 7 is an illustration depicting surface modifying macromolecule IX-aof the invention.

FIG. 8 is an illustration depicting surface modifying macromolecule X-aof the invention.

FIG. 9 is an illustration depicting surface modifying macromolecule X-bof the invention.

FIG. 10 is an illustration depicting surface modifying macromoleculeXI-a of the invention.

FIG. 11 is an illustration depicting surface modifying macromoleculeXI-b of the invention.

FIG. 12 is an illustration depicting surface modifying macromoleculeXII-aof the invention.

FIG. 13 is an illustration depicting surface modifying macromoleculeXII-b of the invention.

FIG. 14 is an illustration depicting surface modifying macromoleculeXIII-a of the invention.

FIG. 15 is an illustration depicting surface modifying macromoleculeXIII-b of the invention.

FIG. 16 is an illustration depicting surface modifying macromoleculeXIII-c of the invention.

FIG. 17 is an illustration depicting surface modifying macromoleculeXIII-d of the invention.

FIG. 18 is an illustration depicting surface modifying macromoleculeXIV-a of the invention.

FIG. 19 is an illustration depicting surface modifying macromoleculeXIV-b of the invention.

FIGS. 20A and 20B show an exemplary hollow fiber and an exemplary bundleof fibers. FIG. 20A is a scanning electron micrograph of a single hollowfiber depicting the outer surface, the inner surface, and the fiberthickness. FIG. 20B is an illustration of bundle of hollow fibersarranged in the header part of the dialyzer cartridge with the pottingarea (areas indicated by arrow labeled “Potted area untreated” in theinner lumen of the dialyzer cartridge, including the thick dotted linewithin the inner lumen of the dialyzer cartridge and the areas markedwith an X) exposed.

FIG. 21 is a photograph of an exemplary configuration for in vitro bloodloop analysis and gamma probe reading.

FIG. 22 is a photograph of hemofilters after a blood loop procedure.

FIG. 23 is a graph showing average header pressure (ΔPr) and γ-countprofiles for control versus VII-a and XI-a (n=6).

FIGS. 24A and 24B are photographs of hemofilters from Experiment 4 inExample 5, as described herein. FIG. 24A shows thrombi formed at theinlet of the hemofilters. FIG. 24B shows thrombi formed at the outlet ofthe hemofilters.

FIGS. 25A-25C are photographs from Experiment 4 in Example 5, asdescribed herein, which show extensive coagulation. FIG. 25A showsthrombi formed at the inlet of the control hemofilter (no surfacemodification). FIG. 25B shows thrombi formed at the outlet of thecontrol hemofilter (no surface modification). FIG. 25C shows residue onthe sieve after draining blood.

FIGS. 26A-26D are photographs of hemofilters from Experiment 5 inExample 5, as described herein. FIG. 26A shows thrombi formed at theinlet of the hemofilters. FIG. 26B shows thrombi formed at the outlet ofthe hemofilters. A control hemofilter showed complete occlusion, whereclose-ups are provided for the inlet (FIG. 26C) and outlet (FIG. 26D)for control.

FIG. 27 shows photographs of the inlet of hemofilters from Experiment1-6 in Example 5, as described herein. Photographs are shown for control(C, top row), VII-a (middle row), and XI-a (bottom row).

FIGS. 28A and 28B are photographs of hemofilters from Experiment 1 inExample 5, as described herein. FIG. 28A shows thrombi formed at theinlet of the hemofilters. FIG. 28B shows thrombi formed at the outlet ofthe hemofilters.

FIGS. 29A and 29B are photographs of hemofilters from Experiment 2 inExample 5, as described herein. FIG. 29A shows thrombi formed at theinlet of the hemofilters. FIG. 29B shows thrombi formed at the outlet ofthe hemofilters.

FIGS. 30A and 30B are photographs of hemofilters from Experiment 3 inExample 5, as described herein. FIG. 30A shows thrombi formed at theinlet of the hemofilters. FIG. 30B shows thrombi formed at the outlet ofthe hemofilters.

FIGS. 31A and 31B are photographs of hemofilters from Experiment 6 inExample 5, as described herein. FIG. 31A shows thrombi formed at theinlet of the hemofilters. FIG. 31B shows thrombi formed at the outlet ofthe hemofilters.

DETAILED DESCRIPTION

The methods and compositions of the invention feature antithrombogenic,extracorporeal blood circuits and components thereof (hollow fibermembranes, potting materials, and blood tubing, etc.) including asynthetic base polymer admixed with from 0.005% to 10% (w/w) surfacemodifying macromolecule. The extracorporeal blood circuit components ofthe invention can be used in therapies such as hemodialysis,hemofiltration, hemoconcentration, hemodiafiltration, and oxygenation,for the treatment of patients with renal failure, fluid overload,toxemic conditions, cardiac failure, or cardiac distress. They can alsobe used for protein separation, plasma filtration, and blood separation.

The selection of the combination of a particular surface modifyingmacromolecule (SMM) and a particular base polymer can be determined bythe methods and protocols described herein. First, the type and amountof SMM to be added to base polymer is determined in part by whether theadmixture forms a single stable phase, where the SMM is soluble in thebase polymer (e.g., separation of the admixture to form two or moredistinct phases would indicate an unstable solution). Then, thecompatibility of the admixture can be tested by various known analyticalmethods. The surface of the admixture as a film or as a fiber can beanalyzed by any useful spectroscopic method, such as X-ray photoelectronspectroscopy (XPS) with an elemental analysis (EA). Data from XPS couldindicate the extent of modification of the surface by migrating SMMs anddata from EA can indicate the extent of modification of the bulkmaterial. Stable admixtures can then be tested to determine thethrombogenicity of the surface under various conditions.

Extracorporeal Blood Circuits

The invention features compositions and methods for reducing theactivation of blood components in contact with any of the parts of anextracorporeal blood circuit (e.g., the blood tubing, the hollow fibermembrane, the potted surface, or the ends of the filter into which theblood tubing attaches) by including a surface modifying macromolecule inone or more of the parts of an extracorporeal blood circuit. Thehemodialysis machine pumps the dialysate as well as the patient's bloodthrough a dialyzer. The blood and dialysate are separated from eachother by a semipermeable hollow fiber membrane, the blood passingthrough the extracorporeal blood circuit of a hemodialysis machine andthe dialysate passing through the dialysate circuit of a hemodialysismachine. Any one or more of the blood-contacting surfaces in theextracorporeal blood circuit of a dialysis machine may be treated with asurface modifying macromolecule as described herein to produce anantithrombogenic surface. The medical separatory device of the inventioncan be an artificial kidney of the hollow fiber type, or a relateddevice, such as hemofilter, blood oxygenator, or other separator ofimpurities from a body.

The devices include a dialysate chamber, and a pair of spaced apart dripchambers attached to each end of the dialysate chamber. Each dripchamber terminates in a port leading to blood tubing, which ultimatelyexit and enter a subject undergoing hemodialysis. The dialysate chamberis provided with conventional inlet and outlet dialysate ports andsurrounds a bundle of axially extending hollow semipermeable fibers.

The fiber bundle contains thousands (e.g., 3,000 to 30,000) individualfibers which may formed from cellulose (e.g., made by deacetylatingcellulose acetate as taught in U.S. Pat. No. 3,546,209), celluloseacetate, cellulose ester, polyesters, polyamides, polysulfone, or anyother hollow fiber membrane known in the art. Typically, the fibers arefine and of capillary size which typically ranges from about 150 toabout 300 microns internal diameter with a wall thickness in the rangeof about 20 to about 50 microns.

Referring to FIG. 1, a typical extracorporeal blood circuit 100 includestubing through which the blood flows and components for filtering andperforming dialysis on the blood.

Blood flows from a patient 105 through arterial tubing 110. Blood dripsinto a drip chamber 115 where a connecting tube from the drip chamber115 attaches to a sensor 125 on a hemodialysis machine that determinesthe pressure of the blood on the arterial side of the extracorporealblood circuit. A pump 120 forces the blood to continue along the paththrough the extracorporeal blood circuit. A dialyzer 130 separates wasteproducts from the blood.

After passing through the dialyzer 130, the blood flows through venoustubing 140 into a second drip chamber 150. The drip chamber 150 canfunction as an air trap. Free gases in the blood may be able to escapeinto the drip chamber 150 before the blood continues to the patient. Asensor 170 is in communication with air in the drip chamber through tube165. The sensor 170 can determine the pressure on the venous side of theextracorporeal blood circuit.

Heparin 160 can be added to the blood in the drip chamber 115. Whenblood is exposed to oxygen, the blood begins to clot. The drip chamber150 may include a filter for preventing any clots from exiting the dripchamber 150 and entering the patient 105. The blood continues from thedrip chamber through venous tubing 180 and through a bubble detector 175before returning to the patient 105.

Any of the blood contacting components of the extracorporeal bloodcircuit can be modified with a surface modifying macromolecule asdescribed herein to produce an antithrombogenic surface. Theextracorporeal blood circuit can be useful for hemodialysis, asexplained above, and can also be applied for other therapies involvinghemoconcentration, oxygenation, protein separation, plasma filtration,and blood separation.

Surface Modifying Macromolecule

Illustrations of VII-a to XI-b are shown in FIGS. 2-19. For all of theSMMs, the number of soft segments can be any integer or non-integer toprovide the approximate theoretical molecule weight of the soft segment.For compounds of formulas (XII) and (XIII), the number of hydrogenatedalkyl moieties can be any integer or non-integer to provide theapproximate theoretical molecule weight of the soft segment. Examples ofXII-a, XII-b, XIII-a, XIII-b, and XIII-c include SMM's, where x=0.225,y=0.65, and z=0.125. For compounds of formula (XI), the number of firstblock segments and second block segments can be any integer ornon-integer to provide the approximate theoretical molecule weight ofthe soft segment. Examples of XI-a and XI-b include SMM's, where m=12 to16 and n=12 to 18.

Table 1 shows the SMM distribution of hard segments, soft segments, andfluorinated end-groups (F end groups). Table 1 also shows the ratio ofhard segment to soft segment, which range from 0.16 to 1.49.

TABLE 1 Ratio: % Soft Seg % Hard Seg % F End Hard/Soft SMM's MW Theo(Diol) (Isocyanate) Groups segment VII-a 2016 47.21 16.68 36.11 0.35VIII-a 3814 25.78 30.59 43.63 1.19 VIII-b 3545 27.73 31.18 41.09 1.12VIII-c 3870 25.64 37.01 37.35 1.44 VIII-d 4800 39.59 30.07 30.34 0.76IX-a 3515 56.89 22.39 20.72 0.39 X-a 4075 23.74 35.42 40.84 1.49 X-b4861 40.35 29.69 29.96 0.74 XI-a 5562 53.94 19.87 26.19 0.37 XI-b 590050.85 24.46 24.69 0.48 XII-a 3785 64.60 13.90 22.00 0.22 XII-b 637276.20 12.40 11.40 0.16 XIII-a 5259 46.18 22.18 31.64 0.48 XIII-b 553643.87 26.07 30.06 0.59 XIII-c 5198 46.72 21.26 32.01 0.46 XIII-d 522740.55 27.61 25.38 0.68 XIV-a 5097 38.76 28.59 32.65 0.74 XIV-b 545046.79 26.48 26.72 0.57Hollow Fiber Membranes

Hydrophobic polymers have been a popular choice as polymeric materialsin hollow fiber spinning e.g. polysulfones, aromatic polyimides, andamides. Any base polymers described herein can be used as a hydrophobicpolymer for hollow fiber spinning. For hemodialysis, hollow fibermembranes are often made from natural cellulose, cellulose derivatives(e.g. cellulose di-or tri-acetate), or synthetic polymers (e.g.,polysulfones, polyacrylonitrile, or polyamides, among others), which areselected for their biocompatibility. However, none of these materialshave proven to provide the desired antithrombogenicity that is needed toreduce the reliance upon anticoagulants.

In particular, polysulfones (PS) are synthetic hydrophobic polymers thatare widely used in hollow fiber membranes due to their excellent fiberspinning properties and biocompatibility. However, pure hydrophobic PScannot be used directly for some applications, e.g., dialysis membranes,as this will decrease the wetting characteristics of the membrane in anaqueous environment and affect the wetting properties essential for theclearance of toxins. To address this problem, polyvinylpyrrolidone (PVP)is typically added to the PS as a pore forming hydrophilic polymer, mostof which dissolves and is lost during the hollow fiber spinning processand hydrophilically modify the PS to make it suitable as a semipermeablemembrane. Although some of the PVP remains in the fiber this is notsufficient as clotting still occurs during dialysis requiring heparinanticoagulants or saline flushes of the dialyzer to clear the blockage.

The methods and compositions of the invention address these issues byincluding a surface modifying macromolecule in the hollow fibermembrane. The surface modifying macromolecule migrates to the surface ofthe hollow fiber membrane (both inner lumen and outer surface during thespinning process) to occupy the top 10 microns of the hollow fiber.

Manufacture of Hollow Fiber Membranes

A porous hollow fiber membrane adapted for use in the methods of theinvention, e.g., kidney dialysis, should be capable of removing lowmolecular weight uremic substances while retaining useful substancessuch as albumin. Such porous hollow fiber membranes are produced usingprocesses adapted to accurately control the pore diameter in the poroushollow fiber membrane. The pore diameter of the hollow fiber membranecan depend upon the composition of the spinning solution, composition ofthe core solution, draft ratio, liquid composition for membranecoagulation, temperature, humidity, among other factors. The compositionof the core solution is an important factor as the combination and themixing ratio of the solvent and the nonsolvent in relation to themembrane-constituting polymer determine the coagulation rate, and hence,the morphology of the interior surface of the hollow fiber membrane.

Various processes are known in the art for the production of hollowfiber membranes (see, for example, U.S. Pat. Nos. 6,001,288; 5,232,601;4,906,375; and 4,874,522, each of which is incorporated herein byreference) including (i) processes wherein a tube-in-tube type orificeis used and the spinning solution is extruded from the outer tube (i.e.,from the annular space defined between the inner and outer tubes) andthe core solution is ejected from the inner tube; (ii) by extruding thespinning solution into air, allowing the filament to fall down bygravity, passing the filament through a coagulant bath for coagulation,and washing and drying the filament (dry-wet spinning); (iii) by using abath including an upper layer of a non-coagulating solution and a lowerlayer of a coagulating solution, and extruding the spinning solutiondirectly into the non-coagulating solution and passing the filamentthrough the coagulating solution; (iv) by using a bath including anupper layer of a coagulating solution and a lower layer of anon-coagulating solution, and extruding the spinning solution directlyinto the non-coagulating solution and passing the filament through thecoagulating solution; (v) by extruding the spinning solution directlyinto a non-coagulating solution and passing the filament along theboundary between the coagulating solution and the non-coagulatingsolution; and (vi) by extruding the spinning solution from the orificesurrounding a non-coagulating solution and passing the filament througha coagulating solution.

In such processes, pore diameter of the hollow fiber membrane iscontrolled by adjusting the rate and the extent of the coagulation ofthe extruded spinning solution through the use of a coagulation solutionwhich promotes the coagulation of the spinning solution (a non solventfor the spinning solution) and a non-coagulation solution which inhibitsthe coagulation of the spinning solution (a solvent for the spinningsolution) either separately or in a mixture.

For use in the compositions and methods of the invention, a typicalspinning solution will include a base polymer (e.g., a polysulfone), ahydrophilic pore forming agent (e.g., polyvinylpyrrolidone, ethyleneglycol, alcohols, polypropylene glycol, or polyethylene glycol), asolvent for the polymer (i.e., dimethylformamide, dimethylsulfoxide,dimethylacetamide, N-methylpyrrolidone, or mixtures thereof), and asurface modifying macromolecule.

The hollow fiber membranes of the invention can be produced, forexample, by extruding the spinning solution from a tube-in-tube typeorifice of the spinner in a coagulation solution to form the hollowfiber membrane. The polymer-containing spinning solution is extrudedfrom the outer tube (i.e., annular space defined between the inner andouter tubes) to form a cylindrical filament having an inner bore and thecore solution for coagulation of the spinning solution is extruded fromthe inner tube of the orifice into the inner bore of the filament. Inthis process, the filament may be directly extruded into the coagulationsolution, or extruded into air and then drawn to the coagulationsolution. As noted above, the spinning solution is supplemented with ahydrophilic pore forming agent and a surface modifying macromolecule andthe resulting hollow fiber membrane contains the surface modifyingmacromolecule on its surface.

The viscosity of the spinning solution can be modified as needed. Forexample, by adding a thickener (e.g., polyvinylpyrrolidone (PVP),polyethylene glycol (PEG), or polypropylene glycol) to increaseviscosity, or by adding an aprotic low boiling solvent (i.e.,tetrahydrofuran, diethylether, methylethyl ketone, acetone, or mixturesthereof) to the spinning solution to reduce viscosity. An aprotic lowboiling solvent may also be included to increase the solubility of thesurface modifying macromolecule in the spinning solution.

The spinning solution is extruded to form the shape of a filament whichis precipitated using a coagulating solution, resulting in formation ofthe desired porous hollow fiber. The coagulating solution may include anonsolvent or a mixture of a nonsolvent and a solvent for the basepolymer of the spinning solution. Typically the nonsolvent used for thecoagulating solution is an aqueous solution.

After the porous hollow fiber is formed, it may be passed through asecond rinsing bath. The porous hollow fiber may then be processedfurther, e.g., cutting, bundling, and drying, and made into a poroushollow fiber membrane suitable, e.g., for use in a dialyzer.

Potted Bundles of Hollow Fiber Membranes

The invention features compositions and methods for reducing theactivation of blood components in contact with the potting material of afilter (e.g., as part of a blood purification device, such as ahemodialysis, hemodiafiltration, hemofiltration, hemoconcentration, oroxygenator device) by including a surface modifying macromolecule in thepotting material at the time that the hollow fiber membranes are potted.

In order to filter or permeate with hollow fiber membranes, a largenumber of thin hollow fibers must be potted (i.e., fixed) to a header ofan encasement such that their inner surfaces are each completely sealedto the inside of the encasement but their lumens are open to pass bloodfrom a first potted end to a second potted end of a filter. Pottingmaterials are an important integral part of blood purification filter asthese are cured polymer materials (usually a polyurethane) that act as aglue to hold the hollow membrane fiber bundles (e.g., numbering up to20,000) firmly at the ends inside the cartridge of the dialyzer, whileat the same time leaving the ends of the hollow fibers open to allow forpassage of blood into the fibers for filtration purposes. Holding thesenumerous fiber bundles inside an encasement and ensuring that each andevery hollow fiber is properly aligned along the axis of the cartridgeis a necessary step in a filter assembly.

The potted walls formed at either end of a blood purification filter isan area prone to turbulent blood flow under shear conditions whichcauses activation of the blood components and first initiate thrombusformation which can adversely affect blood flow and filter function.This problem is not ameliorated by the use of antithrombogenic hollowfiber membranes as the ends of the hollow fiber membranes are only avery small portion of a typical wall surface (e.g., ca. 18% of the wallsurface), followed by hollow lumen (e.g., ca. 16% of the wall surface),and a large amount of potting material (e.g., ca. 66% of the wallsurface). There is a need to address this larger area where dynamicblood flow takes place and where most of thrombus starts that may leadto occlusion of the filters. There is a need for hollow fiber membranesand blood filtration devices that have reduced thrombogenicity.

Potting materials can be thermoset polymers formed by mixing two or morecomponents to form a cured resin (i.e., typically a polyurethane). Toproduce an antithrombogenic potting material of the invention a surfacemodifying macromolecule is added to at least one of the components ofthe potting material prior to mixing to form the cured resin.

The surface modifying macromolecules can be incorporated into anypotting material known in the art. For example, surface modifyingmacromolecules can be incorporated into polyurethane potting materialsformed from an isocyanate-terminated prepolymer, the reaction product ofa polyol and a polyisocyanate, and cured with one or more polyfunctionalcrosslinking agents have been described in the art. Potting materialsthat can be used in the methods, compositions, and dialysis systems ofthe invention include those described in U.S. Pat. Nos. 3,362,921;3,483,150; 3,362,921; 3,962,094; 2,972,349; 3,228,876; 3,228,877;3,339,341; 3,442,088; 3,423,491; 3,503,515; 3,551,331; 3,362,921;3,708,071; 3,722,695; 3,962,094; 4,031,012; 4,256,617; 4,284,506; and4,332,927, each of which is incorporated herein by reference.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how themethods and compounds claimed herein are performed, made, and evaluated,and are intended to be purely exemplary of the invention and are notintended to limit the scope of what the inventors regard as theirinvention.

EXAMPLE 1 Illustration and Calculation of Potting Area

FIG. 20A is a scanning electron micrograph of a single hollow fiber.FIG. 20B is an illustration of a hollow fiber bundle. FIGS. 20A-20Bhighlight the ability of the fiber bundle to provide an antithrombogenicsurface area when in contact with blood. Based upon the dimensions ofthe potted area and the fiber, it can be estimated that if only thehollow fiber membranes are modified as described herein, then only ˜18%of the header area occupied by the fibers (depicted by circles withthick lines within the dialyzer cartridge) is modified with the surfacemodifying macromolecules (SMM) for providing the antithrombogeniceffect. This leaves ˜66% of the area including the potted partunmodified and prone to thrombus formation when in contact with bloodduring hemodialysis. Accordingly, this invention features a method oftreating this ˜66% of the potted part (an integral part of the fiber)also with surface modifying macromolecules to obtain a header surfacethat is antithrombogenic, minimizes blood activation, reduces bloodcoagulation, and reduces the incidence of hemofilter occlusion.

EXAMPLE 2 Surface Modifying Macromolecule in Films of PS/PVP PolymerBlends

Films were prepared to demonstrate the surface composition in themixtures from which the hollow fiber membranes of the invention can bemade. A surface modifying macromolecule (SMM, 5 wt %), polysulfone (PS,10 wt %) and polyvinylpyrrolidone (PVP, 5 wt %) were dissolved in amixture of dimethylacetamide and tetrahydrofuran (ca. 80 wt %). Filmshaving a thickness of 254 μm were cast on Teflon substrates and werethen dried and analyzed for surface Fluorine and Nitrogen content. Theresults are provided in Table 2 for the four solution cast formulationfilms that were analyzed, each utilizing a different surface modifyingmacromolecule.

TABLE 2 XPS in PS/PVP/SMM Films EA of SMM (Surface) (Bulk) SMM # % F % N% F % N VIII-a 42.77 4.23 33.2 5.07 VIII-b 43.82 4.39 23.29 6.66 XI-a37.34 4.93 15.94 3.9 XIII-a 42.75 4.05 20.63 3.49

The surface fluorine content is provided by the X-ray photoelectronspectroscopy (XPS) results for the four films, while the elementalanalysis (EA) of the bulk (neat) SMM is provided for comparison. Thedifference in XPS and EA data for percent fluorine content results fromthe migration of the oligofluoro groups of the surface modifyingmacromolecule to the surface of the film. The percent nitrogen contentat the surface reflects the presence of the hydrophilic urethane portionof the surface modifying macromolecule at the surface of the film inaddition to the presence of the polyvinylpyrrolidone.

EXAMPLE 3 Surface Modifying Macromolecule in Fibers of PS/PVP PolymerBlends

Fibers were also analyzed for Fluorine and Nitrogen content. The resultsare provided in Table 3 for the four solution spun fibers that wereanalyzed, each utilizing a different surface modifying macromolecule(VII-a, VIII-a, IX-a, and XI-a).

TABLE 3 SMM XPS (OS) XPS (IS) EA (Fibers) Fibers % F % N % F % N % F (x)% N VII-a 12.06 4.02 10.79 2.33 0.83 (4)^(a) 0.50 VIII-a 5.14 4.15 8.682.90 0.74 ((3)^(b) 0.52 IX-a 0.78 2.9 2.76 1.51 0.17 (2)^(b) <0.50 XI-a1.35 3.11 1.71 1.39 0.27 (1.6)^(c) <0.50 Si = 1.51% Si = 2.38% Control0.00 4.12 0.00 1.47 0 (0) <0.5 Polysulfone/PVP Fibers ^(a)Targetincorporation of VII-a = 6% ^(b)Target incorporation of VIII-a & IX-a =4% ^(c)Target incorporation of XI-a = 3%

The X-ray photoelectron spectroscopy (XPS) data indicated that all ofthe SMM modified fibers have surface fluorine to various degrees both inthe inner surface (IS) that actually comes in contact with blood duringhemodialysis and the outer surface (OS).

Table 3 also provides the elemental analysis (EA) of the SMM's and the %F in the bulk, which indicates the amount of the additive incorporatedinto the fibers as compared to the targeted incorporation amount. ForVII-a, the EA of the % F shows that of the 6 wt % additive incorporationonly 4 wt % was actually present. This loss of ˜33% can be attributed tothe harsh conditions of the fiber spinning process, which involvesspinning solvent mixtures that dissolves some of the SMM at the sametime that it dissolves the pore forming polyvinylpyrrolidone (PVP). Thisis true for VIII-a, IX-a, and XI-a and is reflected in the differencebetween the target incorporation and the actual incorporation that iscalculated from the elemental analysis. However, all the SMM's no mattertheir final concentration are robust enough to remain in sufficientquantities to provide significant impact on the surface properties,which can be reflected in the antithrombogenic properties evidenced inthe blood loop studies in Example 5.

Table 3 shows that for the commercial control PS/PVP fibers (notmodified with SMM) the XPS results show an absence of Fluorine. Thenitrogen content in the commercial fiber comes from the PVP that remainsafter most of it is washed away during the spinning process. The amountof PVP remaining in the unmodified and SMM modified fibers will alsovary.

Considering the XPS results of the inner surface of the fibers (IS)which comes in contact with the blood, Table 3 shows that for VII-a,VIII-a, IX-a, and XI-a the % F (hydrophobic groups) range from1.71%-10.79% and the % N (hydrophilic groups) are in the range1.39%-2.90%. As determined from the data from Table 3, the ratio of % Fto % N includes from 1.23-4.63 and possible ranges for the ratio of % Fto % N include from 1.20 to 10.0. As provided in Table 1, the ratio ofhard segments to soft segments includes from 0.16-1.49 and possibleranges for this ratio of hard segments to soft segments include from0.15 to 2.0.

While VII-a and XI-a performed the best in this series as shown inExample 5, VIII-a and IX-a did not have any major failures, compared tothe control nor did the failures result in major occlusion of thefilters. Unlike the control, filters modified with VII-a, VIII-a, IX-a,or XI-a did not show such large variation in the header pressures andγ-count (as compared to the standard error in Table 6.).

EXAMPLE 4 Surface Modifying Macromolecule in Potting Materials

Sample disks were prepared to demonstrate the surface composition in thepolymer material including the potted area.

A commercially available potting compound GSP-1555 from GS polymers Inc.was used as the potting material. It is a two part system consisting ofPart A (HMDI based diisocyanate) and Part B (a polyol). Four SMM'sdesignated as VII-a, VIII-a, IX-a, and XI-a (structure depicted in FIGS.2-5) were admixed with the GSP 1555 potting material as shown in Table4. VII-a was used in two concentrations of 1% and 2%, respectively. Allother SMM's, i.e., VIII-a, IX-a, and XI-a, were prepared in only 2%(w/w) concentration according to the following method.

To the GSP 1555 precursor polyol was added the SMM in a 40 ml plasticfalcon tube with thorough mixing. The mixture was dissolved in a volumeof THF. The GSP 1555 precursor diisocyanate was then added, and thereaction mixture was stirred. The resulting GSP 1555 potting compoundcontaining SMM was allowed to cure at room temperature for 24-48 hours.The cured mixture was then dried under vacuum for 48 hours to remove anyresidual solvent from the samples.

TABLE 4 GSP 1555 2A:1B Part A Part B Conc of Conc of SMM # (HMDI)(Polyol) A:B SMM SMM Form (g) (g) in Sol. (%) (g) in (A:B) % VII-a 6.73.3 20 0.1 1 VII-a 6.7 3.3 20 0.2 2 VIII-a 6.7 3.3 20 0.2 2 IX-a 6.7 3.320 0.2 2 XI-a 6.7 3.3 20 0.2 2

The samples were cut into appropriate sizes and submitted for XPS. TheXPS results are provided in Table 5. Values of the atomic % Fdemonstrate that all parts of the potted materials (i.e., the topsurface and new surfaces generated after cutting) have been modifiedwith the additive. That the cut portions of the potted materials havebeen modified with the additive is important, because production of afilter from a bundle of potted hollow fiber membranes typically includesgenerating a new surface as the potted portion of the bundle is cut toproduce a smooth finish to expose the hollow fiber openings. Values ofthe atomic % F also demonstrate that migration of the SMM to a surfaceis a dynamic process and occurs at all surfaces, including thosesurfaces newly generated. For example, VII-a was incorporated at 1%(w/w) to produce a top portion which displays a surface that is 30%fluorine. After heating at 60° C. for 24 hours to increase the amount ofsurface modifying macromolecule near the surface of the wall, the % Fcontent at the surface was reduced to ˜13%. After cutting the sample theXPS showed that the cut surface displays a surface that is ˜7% fluorine,which upon heating at 60° C. for 24 hours is increased to ˜26% fluorine.Thus, the potting material surface of the invention can be heated ifthere is insufficient fluorine at a freshly cut surface. Similarobservations were made for the other SMM's. This also demonstrates thatSMM's can migrate through cured or thermoset polymers.

TABLE 5 Samples % F % N % Si Control 1 -T¹   3.51 ⁵ 4.42 0.49 GSP15551-T60²  0.36 4.40 0.88 polyurethane 1-C³  0.60 4.68 1.03 # 1 1-C60⁴ — —— VII-a 2 -T 30.23 3.45 0.31 1% 2-T60 13.24 3.18 0.37 # 2 2-C  6.77 3.960.41 2-C60 26.10 3.32 0.24 VII-a 3-T 18.00 3.80 0.09 2% 3-T60 27.00 3.310.19 # 3 3-C 12.60 3.16 0.16 3-C60 41.93 3.62 0.01 4-T 28.90 6.31 1.79VIII-a 4-T60 31.40 6.66 0.78 2% 4-C 23.88 5.54 1.50 # 4 4-C60 22.75 5.931.04 5 -T  3.00 3.29 0.26 IX-a 5-T60  9.10 2.69 0.75 2% 5-C  7.47 3.931.42 # 5 5-C60 11.08 2.99 0.47 6-T 36.71 5.72 0.00 XI-a 6-T60 42.31 5.250.02 2% 6-C 26.19 6.07 0.17 # 6 6-C60 33.35 5.81 0.01 ¹T = Top portionof sample at ambient temperature. ²T60 = Top portion of sample at 60°C., 24 hours. ³C = Cut portion of sample at ambient temperature. ⁴C60 =Cut portion of sample at 60° C., 24 hours. ⁵ Control should be devoid offluorine. Here a 3% F content indicates contamination.

EXAMPLE 5 In Vitro Assessment of Hemofilter Thrombosis

Thrombotic surface activity of hemofilters was assessed usingcommercially available hemofilters in response to heparinized bovineblood. Hemofilters were surface modified with VII-a, VIII-a, IX-a, orXI-a and compared with control (hemofilter that was not surfacemodified).

Materials

Commercially available hemofilters containing PS/PVP were used as thecontrol. Four surface modifying macromolecules (SMM's) of VII-a, VIII-a,IX-a, and XI-a (as shown in the Figures) having various chemicalconstituents were used to modify the commercial hemofilters, which wereused as the test samples together with the control filters. Commercialfilters modified with VII-a had 4% additive incorporation. Commercialfilters modified with VIII-a had 3% additive incorporation. Commercialfilters modified with IX-a had 2% additive incorporation. Commercialfilters modified with XI-a had 1.6% additive incorporation. A total of30 filters were analyzed in the study. Heparinized bovine blood (2units/ml) was used for each experiment, where the study included 3 or 6cows. QC release tests were performed on the modified filters fordialyzer function and assessment of fiber dimensions. These werecompared to the control filters.

Methods

An in vitro assessment of hemofilter thrombosis was made using astandard blood loop system and protocol (see Sukavaneshvar et al.,Annals of Biomedical Engineering 28:182-193 (2000), Sukavaneshvar etal., Thrombosis and Haemostasis 83:322-326 (2000), and Sukavaneshvar etal., ASAIO Journal 44:M388-M392 (1998)).

Briefly, the following protocol was used. The blood loop system includeda reservoir, a pump, a hemofilter, and tubing to form a closed flowloop. The loop system was primed with phosphate buffered saline (PBS) at37° C. and circulated for 1 hour before starting an experiment, andpressure was measured at the pressure port between the pump and thehemofilter.

Approximately 10 liters of fresh bovine blood was obtained from a singleanimal for each experiment and heparinized (typical concentration=2U/ml). The experiments were conducted within 8 h of blood collection.Radiolabeled, autologous platelets (with ¹¹¹Indium) were added to theblood prior to the commencement of the study. The PBS in the reservoirwas replaced with blood, and pressure was monitored. Blood circulationin the loop system was typically maintained for 1-2 hours (unlessterminated due to significant pressure build-up, as monitored by apressure gauge). At the end of the experiment, hemofilters werephotographed, and γ-count was measured at the inlet, outlet, and middleof the hemofilter using a γ-probe.

FIG. 21 shows the experimental set-up for the in vitro blood loopanalysis and the configuration of the hemofilters for the study. Thefigure also shows the arrangement of the γ-probe reading for thehemofilters, where measurements were determined end-on and in the middleof the hemofilters. The γ-probe readings for the radiolabeled plateletswere determined after the filters were exposed to the blood flow andrinsed with PBS solution to remove any residual blood. FIG. 22 shows anarrangement of the hemofilters after the blood loop procedure, justbefore the header caps (top and bottom caps) are unscrewed to visuallyexamine for thrombus.

Results & Discussion

Table 6 shows the results of the in vitro study of hemodialysis filtersthrombus for control (C1) versus VII-a, VIII-a, IX-a, and XI-a. Table 6also shows the header pressure change (ΔP) at the inlet (top cap in FIG.22) and the γ-probe readings of the radiolabeled activated platelets atthe inlet (top cap in FIG. 22), middle, and outlet (bottom cap in FIG.22) regions of the hemofilters after blood contacting for Experiments1-6. In Experiment 1, the first filter to fail after 25 minutes wasIX-a, where the header pressure was 180 mm Hg. This is called thefailure or occlusion time. Failure here means when the header pressurereached ≧175 mm Hg over the base pressure. At this point, the γ-count ofthe activated platelets was 3582, while it was 3250 in the middle and2223 at the outlet. VII-a performed the best in this experiment not onlyamongst the SMM's but also compared to the control with the lowestheader pressure of 20 vs. 53 mm Hg (control). The γ-count at this pointwas 2631. However, the γ-count in the middle was higher (at 4534) andlower in the outlet (at 2454). The higher γ-count in the middle may beindicative of loosely bound micro-thrombi that slips through into thefiber (due to the additive nature of the SMM), which does not allow thethrombi to accumulate. The higher concentration of activated plateletsin the middle of the filters is generally true for most of the SMMmodified filters, as is evident in Experiments 1, 2, 3, 5, and 6. Inthis experiment (Experiment 1), XI-a modified filters also performedwell with a header pressure of 35 mm Hg, as compared to the control.

TABLE 6 Header pr γ-probe read. (cpm) Expt Δ Pr R M B Total RadiationFlow = 200 ml/min Filters # Inlet (red) Inlet Middle Outlet cpm Expt 1C1 53 2231 2165 1410 4396 Occlusion time VII-a 20 2631 4534 2454 7165 t= 25 mins VIII-a 53 2667 3683 2049 6350 IX-a^(a) 180 3582 3250 2223 6832XI-a 35 2701 4631 2527 7332 Expt 2 C1 86 1905 1536 1078 3441 Occlusiontime VII-a 158 3293 3557 2085 6850 t = 57 mins VIII-a^(a) 185 2623 28061512 5429 IX-a 155 2413 2510 1821 4923 XI-a 176 2791 2942 1770 5733 3 C1154 20339 4624 2619 24963 Occlusion time VII-a 21 6554 4608 2662 11162 t= 30 mins VIII-a^(a) 227 19816 5799 2692 25615 IX-a 217 19982 6876 393026858 XI-a 36 7660 2962 1867 10622 4 C1^(a) 926 17982 4342 5707 22324Occlusion time VII-a 9 1915 2547 1479 4452 t = 8 mins VIII-a 12 19412106 1311 4047 IX-a 133 6433 3893 2554 10326 XI-a 51 1404 1993 1196 33975 C1^(a) 362 4836 2747 1984 7583 Occlusion time VII-a −3 2255 3442 23015697 t = 10 mins VIII-a 8 5577 8065 4835 13642 IX-a 8 905 917 913 1822XI-a −5 1012 1098 435 2110 6 C1 33 2465 1717 1082 4182 Occlusion timeVII-a 41 5091 5762 2967 10853 t = 40 mins VIII-a^(a) 222 5019 3664 18508683 IX-a 35 2280 2348 1519 4628 XI-a 63 3644 3186 1673 6830 ^(a)Filtersthat failed in each experiment

In Experiment 2, VIII-a failed within 57 minutes with a header pressureof 185 mm Hg. In this experiment, the control performed the best withthe lowest header pressure at 86 mm Hg compared to VH-a or IX-a. Thecorresponding γ-counts are also shown in the Table 6. However, in thenext 4 experiments, VII-a performed the best among all the filterstested with the lowest header pressure, except in Experiment 6 where theheader pressure for XI-a was slightly higher than the control. Theγ-counts at the header inlet are also reflective of its performance.XI-a performed second best in this series. Experiments 4 and 5 showedsome interesting results, where the control filters failedcatastrophically within 8 and 10 minutes, respectively, with massivefibrin rich thrombus and complete occlusion of the filters. Table 6shows how high the pressure was (926 and 362 mm Hg) of the controlfilters relative to the SMM modified filters and the corresponding highplatelet count at this point. None of the SMM modified filters failedwithin 10 minutes in any of the experiments nor did they reach such highpressures at any point during the entire analysis.

Table 7 shows the average header pressure and the γ-count at the inletfor the control and VII-a, VIII-a, IX-a, and XI-a modified filters withthe corresponding standard deviation and standard error for sixexperiments (n=6). The high value of the standard error (STE) for thecontrol in comparison to any of the SMM's is also an indication of thelarge variability in the control filter performance. The table alsoindicates that the header pressures (inlet) of VII-a and XI-a had theleast variability, evident from the STE values of 24 and 25respectively. The γ-counts of the activated platelets at the headerinlet (Table 7) also show a much lower STE for VII-a and XI-a comparedto the control filters. Both these values are in conformity with thefilter performance of VII-a and XI-a vs. control filters.

It should be noted that Experiment 5 in Table 7 shows that the headerpressures of VII-a was-3 mm Hg and XI-a was-5 mm Hg. These are actualvalues in the in vitro analysis due to a pulsating blood flow under highshear stress through the fibers, which can result in a slight negativepressure and should actually be interpreted as ‘0’ for all intents andpurposes.

TABLE 7 Occlusion T Expt. Control VII-a VIII-a IX-a XI-a min HeaderPressure Change -Inlet (Red) 1 53 20 53 180 35 25 2 86 158 185 155 17657 3 154 21 227 217 36 30 4 826 9 12 133 51 8 5 362 −3 8 8 −5 10 6 33 41222 35 63 40 Av 269 41 118 121 59 STD 343 59 105 83 62 STE 140 24 43 3425 Gamma Count - Inlet (Red) 1 2231 2631 2667 3582 2701 2 1905 3293 26232413 2791 3 20339 6554 19816 19982 7660 4 17982 1915 1941 6433 1404 54836 2255 5577 905 1012 6 2465 5091 5019 2280 3644 Av 8293 3623 62745933 3202 Av/10 829.3 362 627 593 320 STD 8514 1824 6791 7130 2388 STE3476 744 2772 2911 975 STE/10 348 74 277 291 97

Table 8 illustrates the time to failure and the corresponding filtersthat failed first in each experiment. It can be seen that in Experiments4 and 5 the control filters failed catastrophically, whereas inExperiment 1, IX-a failed in 25 minutes. In Experiments 2, 3, and 6,VIII-a failed (57, 30, and 40 minutes respectively), but none of thesewere major failures nor did they result in filters becoming fullyoccluded with thrombus. Table 8 also summarizes the header pressure ofthe two best SMM formulations (VII-a and XI-a) and how these comparerelative to the control.

TABLE 8 Parameters Expt 1 Expt 2 Expt 3 Expt 4 Expt 5 Expt 6 Time toFailure 25 57 30 8 10 40 minutes¹ First Filter to IX-a VIII-a VIII-aControl Control VIII-a Fail ΔP at Header (Inlet) for VII-a & XI-aFilters vs Control² VII-a 20 158 21 9 −3 441 XI-a 35 176 36 51  −5 63Control 53 86 154 926³   362³  33 ¹Each experiment was terminated if thepressure was ≧175 mmHg, relative to the baseline pressure. This wasdeemed as filter failure. Control in Expt 4 and 5 failed within 10minutes. ²ΔP denote the change in header pressure relative to thebaseline pressure. ³The filters in Expt 4 and 5 were fully occluded withthrombus

FIG. 23 illustrates graphically the average header pressure and γ-countsof VII-a and XI-a in comparison to the control filters. The error barsare an indication of variability in both the pressure and y readings;both of which are higher in the control vs. VII-a and XI-a. On average,VII-a had 85% less header pressure and XI-a had 78% less header pressurethan the control while the γ-counts were 56% and 61% lower in VII-a andXI-a, respectively, as compared to the commercial control.

FIGS. 24A-24B and FIGS. 25A-25C are thrombus photos of Experiment 4, andFIGS. 26A-26D are thrombus photos of Experiment 5. In these experiments,the control filters failed within 10 minutes or less with massivethrombus formation and filter occlusion. FIGS. 24A-24B and FIGS. 25A-25Cespecially shows that not only the headers had thrombus but there wasthrombus residue on the sieve after the draining of the blood indicativeof hypercoagulation.

FIG. 27 compares the thrombus photos of VII-a and XI-a with controlfilters for all the 6 experiments. From the degree of redness of theheader inlet indicative of red thrombus build-up and plateletactivation, it can be seen that VII-a and XI-a on an average, performedbetter than the control (besides the pressure values).

Thrombus photos were taken of the filter headers at the inlet and outletpositions after the blood loop analysis for all the 6 experiments.Experimental results are shown as thrombus photos for Experiment 1(FIGS. 28A-28B), Experiment 2 (FIGS. 29A-29B), Experiment 3 (FIGS.30A-30B), and Experiment 6 (FIGS. 31A-31B). In all these cases it waseither VIII-a or IX-a failed, but the filters were never occluded unlikethe control in experiment 4 and 5.

In addition, all the SMM modified filters (VII-a, VIII-a, IX-a, or XI-a)were able to be spun into fibers. When assembled into dialyzer filters,the hemofilters were tested, and all were able to function as ahemofilter, as compared to a control hemofilter. In general, all of thehemofilters functioned as a dialyzer.

Conclusions

The in vitro blood loop studies using heparinized bovine blood indicatedthat VII-a and XI-a performed the best among all the filters tested.These two formulations showed no filter failure with the lowest averageheader pressure (>75% less pressure), low average γ-count (>55% less),low thrombus and less thrombogenicity, than the control. Conversely, thecontrol filters performed the worst, failing catastrophically in twoexperiments within 10 minutes. It also had the highest average headerpressure, γ-count and variability of all the filters tested in the 6experiments. VIII-a failed in 3 experiments and IX-a failed in 1experiment, but all of these were within 25-57 minutes and none of thefilters had any major occlusion. All of the hemofilters function as adialyzer in various degrees and adjustments can be made easily toconform to the desired specifications.

Other Embodiments

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are within the claims.

What is claimed is:
 1. A blood tubing comprising a base polymer admixedwith from 0.005% to 10% (w/w) surface modifying macromolecule, whereinsaid blood tubing is antithrombogenic when contacted with blood, asmeasured by y-count, and wherein said surface modifying macromolecule isdescribed by formula:F_(T)—[B-(Oligo)]_(n)-B—F_(T),  (VII) wherein (i) Oligo is polypropyleneoxide having a theoretical molecular weight of from 500 to 2,000Daltons; (ii) B is a hard segment formed from hexamethylenediisocyanate; (iii) F_(T) is a polyfluoroorgano group; and (iv) n is aninteger from 1 to
 10. 2. The blood tubing of claim 1, wherein said basepolymer comprises polyvinyl chloride.
 3. The blood tubing of claim 1,wherein n is an integer from 1 to
 3. 4. The blood tubing of claim 1,wherein F_(T) is a polyfluoroalkyl having a theoretical molecular weightof between 100-1,500 Da.
 5. The blood tubing of claim 1, wherein F_(T)is CF₃(CF₂)_(r)CH₂CH₂—, wherein r is 2-20.
 6. The blood tubing of claim1, wherein F_(T) is CF₃(CF₂)_(s)(CH₂CH₂O)_(x)—, wherein _(X) is 1-10 ands is 1-20.
 7. The blood tubing of claim 1, wherein F_(T) isCH_(m)F_((3−m))(CF₂)_(r)CH₂CH₂— orCH_(m)F_((3−m))(CF₂)_(s)(CH₂CH₂O)_(x)—, wherein m is 0, 1, 2, or 3; _(X)is an integer between 1-10; r is an integer between 2-20; and s is aninteger between 1-20.
 8. The blood tubing of claim 1, wherein F_(T) isformed from 1H,1H,2H,2H-perfluoro-1-decanol;1H,1H,2H,2H-perfluoro-1-octanol; 1H,1H,5H-perfluoro-1-pentanol; or1H,1H, perfluoro-1-butanol, or a mixture thereof.
 9. The blood tubing ofclaim 8, wherein F_(T) is formed from 1H,1H,2H,2H-perfluoro-1-octanol.10. The blood tubing of claim 1, wherein F_(T) is (CF₃)(CF₂)₅CH₂CH₂O—,(CF₃)(CF₂)₇CH₂CH₂O—, (CF₃)(CF₂)₅CH₂CH₂O—, CHF₂(CF₂)₃CH₂O—, or(CF₃)(CF₂)₂CH₂O—.
 11. The blood tubing of claim 1, wherein said surfacemodifying macromolecule is described by formula:

wherein the [CH(CH₃)CH₂O]_(n) unit has a theoretical molecular weight offrom 500 to 2,000 Daltons.
 12. The blood tubing of claim 11, wherein the[CH(CH₃)CH₂O]_(n) unit has Mw of 1000 g/mol.